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1
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Wagner CA, Egli-Spichtig D, Rubio-Aliaga I. Updates on renal phosphate transport. Curr Opin Nephrol Hypertens 2025:00041552-990000000-00234. [PMID: 40357590 DOI: 10.1097/mnh.0000000000001090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
PURPOSE OF REVIEW The kidneys control systemic phosphate balance by regulating phosphate transporters mediating the reabsorption of inorganic phosphate (Pi). At least three different Na+-driven Pi cotransporters are located in the brush border membrane (BBM) of proximal tubule cells, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3) and PiT-2 (SLC20A2). This review will discuss novel aspects of their regulation, pharmacology, and genetics. RECENT FINDINGS Renal NaPi transporters are not only acutely regulated by the phosphaturic hormones parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) but possibly also by further mechanisms. A role of inositol hexakisphosphate (IP6) kinases has been found and their deletion from kidneys causes hypophosphatemia, hyperphosphaturia, and bone demineralization. Inhibitors of NaPis elicit phosphaturia and may reduce levels of PTH and FGF23 in chronic kidney disease (CKD) models. The relevance of renal NaPi transporters is highlighted by loss-of-function mutations in SLC34 transporters and analysis of patients provides new insights into diseases caused by variants. Major manifestations include nephrocalcinosis and -lithiasis, rickets, and variants may predispose to an accelerated decline in kidney function. SUMMARY Renal Pi transporters are regulated, may provide novel drug targets for prevention or treatment of hyperphosphatemia, and contribute to the genetic risk to develop kidney stones and CKD.
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Karagiannidis AG, Theodorakopoulou MP, Iatridi F, Ortiz A, Sarafidis P. A salty symphony: unraveling the tale of uromodulin and sodium sensitivity. J Hum Hypertens 2025; 39:320-333. [PMID: 40164702 DOI: 10.1038/s41371-025-01013-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 02/27/2025] [Accepted: 03/21/2025] [Indexed: 04/02/2025]
Abstract
Uromodulin is a kidney-specific glycoprotein which is uniquely synthesized by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. Among multiple roles in complex physiological and pathological processes, uromodulin mediates renal sodium handling through modulating tubular sodium transporters that reabsorb sodium and therefore is putatively linked to hypertension through generating sodium sensitivity of blood pressure. This review aims to present an updated overview of the role of uromodulin in sodium renal handling and summarize the existing evidence originating from preclinical, genetic, and clinical studies that support a relationship between uromodulin and sodium-sensitive hypertension.
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Affiliation(s)
- Artemios G Karagiannidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta P Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
| | - Pantelis Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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3
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Sánchez-Cazorla E, Temes-Álvarez B, Oliveros-Martínez P, Fortes-González P, García-Murias M, Barcia de la Iglesia A, Carrera N, García-González MÁ. Characterization of recurrent UMOD variants (p.C255Y y p.Q316P) in a Galician cohort: genotype-phenotype correlation and clinical implications. Nefrologia 2025:S2013-2514(25)00058-6. [PMID: 40300987 DOI: 10.1016/j.nefroe.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/22/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND The UMOD gene encodes the uromodulin protein, which plays a crucial role in renal function. Genetic alterations affecting its correct function are mainly related to Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), progressive renal failure and hyperuricaemia, among other variable clinical phenotypes. In the Galician population there are recurrent mutations in this gene, this study aims to phenotypically characterize the recurrent variants to improve the prognosis and management strategies of affected patients. METHODS In a Galician population characterized by high genetic conservation, a retrospective cohort study was conducted with 37 patients from 15 families carrying recurrent variants in UMOD (p.C255Y and p.Q316P, from transcript NM_001008389.3). Clinical data were collected, including renal function, hyperuricemia, hypertension and presence of renal cysts. Genomic analyses were performed by NGS and Sanger sequencing, variant classification were conducted according to ACMG guidelines. Statistical comparisons were performed using Mann-Whitney, Chi-square and Fisher tests, with Benjamini-Hochberg correction for multiple testing. RESULTS The cohort included 28 carriers of p.C255Y and 9 of p.Q316P genetic variants. Both variants affect highly conserved domains with low tolerance to amino acid changes, which alters protein function and has clinical effects in patients. Hyperuricemia was observed in 76% of p.C255Y carriers and 50% of p.Q316P carriers, while interestingly only the first variant was associated with episodes of gout. Renal cysts and hypertension were identified in about half of the patients, independently of variant type. Kaplan-Meier curves suggested an earlier progression to hyperuricemia and advanced chronic kidney disease (CKD) in p.C255Y carriers, although without reaching statistical significance. CONCLUSIONS Recurrent UMOD mutations in a Galician cohort revealed shared clinical features, including hyperuricemia and CKD progression, with phenotypic variability influenced by age and additional genetic modifiers. The findings highlight the prognostic value of genotype-phenotype correlations and the need for tailored clinical management in ADTKD patients.
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Affiliation(s)
- Eloísa Sánchez-Cazorla
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain
| | - Borja Temes-Álvarez
- RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain; Nephrology service, Clinical University Hospital of Ourense (CHUOU), Ourense, Spain
| | - Pilar Oliveros-Martínez
- RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain; Nephrology service, Clinical University Hospital of Santiago de Compostela (CHUS), Santiago de Compostela, Spain
| | - Pedro Fortes-González
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain
| | - María García-Murias
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain
| | - Ana Barcia de la Iglesia
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain
| | - Noa Carrera
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain.
| | - Miguel Ángel García-González
- Group of Genetics and Developmental Biology of Renal Disease, Laboratory of Nephrology, No. 11, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; Genomic Medicine Group, Clinical University Hospital of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain; RICORS 2040 (Kidney Disease), ISCIII, Santiago de Compostela, Spain.
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D’Antonio M, Arthur TD, Gonzalez Rivera WG, Wu X, Nguyen JP, Gymrek M, Woo-Yeong P, Frazer KA. Genetic analysis of elevated levels of creatinine and cystatin C biomarkers reveals novel genetic loci associated with kidney function. Hum Mol Genet 2025; 34:751-764. [PMID: 39927731 PMCID: PMC12010162 DOI: 10.1093/hmg/ddaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/22/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025] Open
Abstract
The rising prevalence of chronic kidney disease (CKD), affecting an estimated 37 million adults in the United States, presents a significant global health challenge. CKD is typically assessed using estimated Glomerular Filtration Rate (eGFR), which incorporates serum levels of biomarkers such as creatinine and cystatin C. However, these biomarkers do not directly measure kidney function; their elevation in CKD results from diminished glomerular filtration. Genome-wide association studies (GWAS) based on eGFR formulas using creatinine (eGFRcre) or cystatin C (eGFRcys) have identified distinct non-overlapping loci, raising questions about whether these loci govern kidney function or biomarker metabolism. In this study, we show that GWAS on creatinine and cystatin C levels in healthy individuals reveal both nonoverlapping genetic loci impacting their metabolism as well as overlapping genetic loci associated with kidney function; whereas GWAS on elevated levels of these biomarkers uncover novel loci primarily associated with kidney function in CKD patients.
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Affiliation(s)
- Matteo D’Antonio
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Timothy D Arthur
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Wilfredo G Gonzalez Rivera
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Ximei Wu
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Jennifer P Nguyen
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Melissa Gymrek
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Department of Computer Science and Engineering, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Park Woo-Yeong
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Daegu, Republic of Korea
| | - Kelly A Frazer
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093, United States
- Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, 9500 Gilman Dr., La Jolla, CA 92093, United States
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Gogoi P, Valan JA. Machine learning approaches for predicting and diagnosing chronic kidney disease: current trends, challenges, solutions, and future directions. Int Urol Nephrol 2025; 57:1245-1268. [PMID: 39560857 DOI: 10.1007/s11255-024-04281-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/05/2024] [Indexed: 11/20/2024]
Abstract
Chronic Kidney Disease (CKD) represents a significant global health challenge, contributing to increased morbidity and mortality rates. This review paper explores the current landscape of machine learning (ML) techniques employed in CKD prediction and diagnosis, highlighting recent trends, inherent challenges, innovative solutions, and future directions. Through an extensive literature survey, we identified key limitations and challenges, including the use of small datasets, the absence of stage-specific predictions, insufficient focus on model interpretability, and a lack of discussions on safeguarding patient privacy in managing sensitive CKD data. We considered these limitations and challenges as research gaps, and this review paper aims to address them. We emphasize the potential of Generative AI to augment dataset sizes, thereby enhancing model performance and reliability. To address the lack of stage-specific predictions, we highlight the need for effective multi-class models to accurately predict CKD stages, enabling tailored treatments and improved patient outcomes. Furthermore, we discuss the critical importance of model interpretability, utilizing methods such as SHAP (SHapley Additive exPlanations) and LIME (Local Interpretable Model-agnostic Explanations) to ensure transparency and trust among healthcare professionals. Privacy concerns surrounding sensitive patient data are also addressed. We present innovative privacy-preserving solutions using technologies, such as homomorphic encryption, federated learning, and blockchain. These solutions facilitate collaboration across institutions while maintaining patient confidentiality and addressing challenges related to limited generalizability and reproducibility in CKD prediction. This review informs healthcare professionals and researchers about advancements in ML for CKD prediction, to improve patient outcomes and address research gaps.
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Affiliation(s)
- Prokash Gogoi
- Department of Computer Science and Engineering, National Institute of Technology Nagaland, Chumukedima, Dimapur, Nagaland, 797103, India.
| | - J Arul Valan
- Department of Computer Science and Engineering, National Institute of Technology Nagaland, Chumukedima, Dimapur, Nagaland, 797103, India
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6
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Zhu H, Wang Y, Li L, Wang L, Zhang H, Jin X. Cell-free DNA from clinical testing as a resource of population genetic analysis. Trends Genet 2025; 41:330-344. [PMID: 39578178 DOI: 10.1016/j.tig.2024.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 11/24/2024]
Abstract
As a noninvasive biomarker, cell-free DNA (cfDNA) has achieved remarkable success in clinical applications. Notably, cfDNA is essentially DNA, and conducting whole-genome sequencing (WGS) can yield a wealth of genetic information. These invaluable data should not be confined to one-time use; instead, they should be leveraged for more comprehensive population genetic analysis, including genetic variation spectrum, population structure and genetic selection, and genome-wide association studies (GWASs), among others. Such research findings can, in turn, facilitate clinical practice, enabling more advanced and accurate disease predictions. This review explores the advantages, challenges, and current research areas of cfDNA in population genetics. We hope that this review can serve as a new chapter in the repurposing of cfDNA sequence data generated from clinical testing in population genetics.
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Affiliation(s)
- Huanhuan Zhu
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China
| | - Yu Wang
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China
| | - Linxuan Li
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China; College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lin Wang
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China
| | - Haiqiang Zhang
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China
| | - Xin Jin
- BGI Research, Shenzhen 518083, China; Shenzhen Key Laboratory of Transomics Biotechnologies, BGI Research, Shenzhen 518083, China; School of Medicine, South China University of Technology, Guangzhou 510641, China; Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan 030001, China.
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7
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Singh A, Bocher O, Zeggini E. Insights into the molecular underpinning of type 2 diabetes complications. Hum Mol Genet 2025; 34:469-480. [PMID: 39807636 PMCID: PMC11891870 DOI: 10.1093/hmg/ddae203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/18/2024] [Accepted: 12/30/2024] [Indexed: 01/16/2025] Open
Abstract
Type 2 diabetes (T2D) complications pose a significant global health challenge. Omics technologies have been employed to investigate these complications and identify the biological pathways involved. In this review, we focus on four major T2D complications: diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, and cardiovascular complications. We discuss advancements in omics research, summarizing findings from genetic, epigenomic, transcriptomic, proteomic, and metabolomic studies across different ancestries and disease-relevant tissues. We stress the importance of integrating multi-omics techniques to elucidate the biological mechanisms underlying T2D complications and advocate for ancestrally diverse studies. Ultimately, these insights will improve risk prediction for T2D complications and inform translation strategies.
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Affiliation(s)
- Archit Singh
- Technical University of Munich (TUM), TUM School of Medicine and Health, Graduate School of Experimental Medicine and Health Sciences, Ismaninger Straße 22, Munich 81675, Germany
- Institute of Translational Genomics, Helmholtz Zentrum München- German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany
- Munich School for Data Science (MUDS), Helmholtz Zentrum München- German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany
| | - Ozvan Bocher
- Institute of Translational Genomics, Helmholtz Zentrum München- German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany
| | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München- German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany
- TUM School of Medicine and Health, Technical University of Munich and Klinikum Rechts der Isar, Ismaninger Straße 22, Munich 81675, Germany
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8
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Liu M, Kim DS, Park S. Gene-Lifestyle Interactions in Renal Dysfunction: Polygenic Risk Modulation via Plant-Based Diets, Coffee Intake, and Bioactive Compound Interactions. Nutrients 2025; 17:916. [PMID: 40077791 PMCID: PMC11901526 DOI: 10.3390/nu17050916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Background: This study aimed to investigate genetic variants associated with the estimated glomerular filtration rate (eGFR) and their interactions with lifestyle factors and bioactive compounds in large hospital-based cohorts, assessing their impact on renal dysfunction risk. Methods: Participants were categorized into two groups based on eGFR: High-GFR (control; n = 51,084) and Low-GFR (renal dysfunction; n = 7617), using an eGFR threshold of 60 mL/min/1.73 m2. Genetic variants were identified through a genome-wide association analysis, and their interactions with lifestyle factors were assessed a using generalized multifactor dimensionality reduction (GMDR) analysis. Additionally, interactions between polygenic risk scores (PRS) and nutrient intake were examined. Results: Low eGFR was associated with higher urinary protein levels (4.67-fold) and correlated with a Western-style diet and with saturated fat, arginine, and isoleucine intakes but not sodium intake. The genetic model for low eGFR included variants linked to energy production and amino acid metabolism, such as rs1047891_CPS1, rs3770636_LRP2, rs5020545_SHROOM3, rs3812036_SLC34A1, and rs4715517_HCRTR2. A high PRS was associated with a 1.78-fold increased risk of low eGFR after adjusting for sociodemographic and lifestyle factors. The PRS from the 6-SNP model interacted with plant-based diets (PBDs) and coffee intake, where individuals with higher PBD and coffee consumption had a lower risk of renal dysfunction. Additionally, CPS1 rs1047891 interacted with vitamin D intake (p = 0.0436), where the risk allele was linked to lower eGFR with low vitamin D intake but not with high intake. Molecular docking showed that vitamin D3 had a lower binding energy to the CPS1 mutant type (-9.9 kcal/mol) than the wild type (-7.5 kcal/mol), supporting a potential gene-nutrient interaction influencing renal function. Conclusions: Middle-aged and elderly individuals with a high genetic risk for renal dysfunction may benefit from a plant-based diet, moderate coffee consumption, and sufficient vitamin D intake.
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Affiliation(s)
- Meiling Liu
- Department of Chemical Engineering, Shanxi Institute of Science and Technology, Jincheng 048011, China;
| | - Da-Sol Kim
- Department of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, 20 Hoseoro97bun-gil, BaeBang-Yup, Asan 41399, ChungNam-Do, Republic of Korea;
| | - Sunmin Park
- Department of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, 20 Hoseoro97bun-gil, BaeBang-Yup, Asan 41399, ChungNam-Do, Republic of Korea;
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9
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Watanabe M, Takimoto HR, Hashimoto K, Ishii Y, Sasaki N. Effectively simplified Adriamycin-induced chronic kidney disease mouse model: Retro-orbital vein injection versus tail-vein injection. Animal Model Exp Med 2025; 8:568-572. [PMID: 39843403 PMCID: PMC11904100 DOI: 10.1002/ame2.12553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
This study aimed to investigate the impact of administration routes in establishing the Adriamycin (ADR)-induced chronic kidney disease (CKD) model. Using BALB/c mice, we compared the effects of conventional tail-vein injection (TV10, 10 mg/kg) to those of retro-orbital sinus (orbital vein) injection (OV10, 10 mg/kg; OV8, 8 mg/kg). The results indicated that the OV10 group exhibited CKD pathology similar to the TV10 group, with both groups demonstrating significantly higher urinary albumin/creatinine ratio (p < 0.05), tubular injury (p < 0.05), and degree of renal fibrosis (p < 0.05) than the OV8 group. No significant differences were observed between the OV10 and TV10 groups in urinary albumin/creatinine ratio, tubular injury, and degree of renal fibrosis. These findings demonstrated that retro-orbital administration of 10 mg/kg ADR induces comparable effects to conventional tail-vein administration. This technique's technical simplicity may improve experimental efficiency, reproducibility, and animal welfare in CKD research. In conclusion, this study validates the utility of retro-orbital injection in CKD model establishment, demonstrating its potential to standardize and improve the reliability of future CKD research protocols.
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Affiliation(s)
- Masaki Watanabe
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary MedicineKitasato UniversityTowadaJapan
| | - Hayato R. Takimoto
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary MedicineKitasato UniversityTowadaJapan
| | - Kazuki Hashimoto
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary MedicineKitasato UniversityTowadaJapan
| | - Yuki Ishii
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary MedicineKitasato UniversityTowadaJapan
| | - Nobuya Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary MedicineKitasato UniversityTowadaJapan
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10
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Liu H, Abedini A, Ha E, Ma Z, Sheng X, Dumoulin B, Qiu C, Aranyi T, Li S, Dittrich N, Chen HC, Tao R, Tarng DC, Hsieh FJ, Chen SA, Yang SF, Lee MY, Kwok PY, Wu JY, Chen CH, Khan A, Limdi NA, Wei WQ, Walunas TL, Karlson EW, Kenny EE, Luo Y, Kottyan L, Connolly JJ, Jarvik GP, Weng C, Shang N, Cole JB, Mercader JM, Mandla R, Majarian TD, Florez JC, Haas ME, Lotta LA, Drivas TG, Vy HMT, Nadkarni GN, Wiley LK, Wilson MP, Gignoux CR, Rasheed H, Thomas LF, Åsvold BO, Brumpton BM, Hallan SI, Hveem K, Zheng J, Hellwege JN, Zawistowski M, Zöllner S, Franceschini N, Hu H, Zhou J, Kiryluk K, Ritchie MD, Palmer M, Edwards TL, Voight BF, Hung AM, Susztak K. Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants. Science 2025; 387:eadp4753. [PMID: 39913582 PMCID: PMC12013656 DOI: 10.1126/science.adp4753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 11/20/2024] [Indexed: 02/17/2025]
Abstract
Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Disease Genetic Scorecard" for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.
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Affiliation(s)
- Hongbo Liu
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Penn-CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Amin Abedini
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Eunji Ha
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Ziyuan Ma
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Xin Sheng
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, Zhejiang, China
- Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Bernhard Dumoulin
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Chengxiang Qiu
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Tamas Aranyi
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Molecular Life Sciences, HUN-REN Research Center for Natural Sciences, Budapest, Hungary
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Shen Li
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicole Dittrich
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Hua-Chang Chen
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ran Tao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Der-Cherng Tarng
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Feng-Jen Hsieh
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
| | - Shih-Ann Chen
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
- National Chung Hsing University, Taichung, Taiwan, ROC
- Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Internal Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
| | - Mei-Yueh Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Department of Internal Medicine, Kaohsiung Medical University Gangshan Hospital, Kaohsiung, Taiwan, ROC
| | - Pui-Yan Kwok
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
- Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Jer-Yuarn Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
| | - Chien-Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
| | - Atlas Khan
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Nita A. Limdi
- Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Theresa L. Walunas
- Department of Medicine, Division of General Internal Medicine and Center for Health Information Partnerships, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Eimear E. Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuan Luo
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Leah Kottyan
- The Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - John J. Connolly
- Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Gail P. Jarvik
- Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, USA
| | - Chunhua Weng
- Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Ning Shang
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Joanne B. Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Josep M. Mercader
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Mandla
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine and Cardiovascular Research Institute, Cardiology Division, University of California, San Francisco, CA, USA
- Graduate Program in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Timothy D. Majarian
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Vertex Pharmaceuticals, Boston, MA, USA
| | - Jose C. Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Mary E. Haas
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Luca A. Lotta
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | | | - Theodore G. Drivas
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Ha My T. Vy
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Girish N. Nadkarni
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Hasso Plattner Institute of Digital Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Mount Sinai Clinical Intelligence Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laura K. Wiley
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Melissa P. Wilson
- Department of Biomedical Informatics, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Christopher R. Gignoux
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Humaira Rasheed
- KGJebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Laurent F. Thomas
- KGJebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway
| | - Bjørn Olav Åsvold
- KGJebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Endocrinology, Clinic of Medicine, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Ben M. Brumpton
- KGJebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Clinic of Thoracic and Occupational Medicine, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Stein I. Hallan
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Nephrology, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Kristian Hveem
- KGJebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jie Zheng
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jacklyn N. Hellwege
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Matthew Zawistowski
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Sebastian Zöllner
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
| | - Nora Franceschini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Hailong Hu
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Jianfu Zhou
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Marylyn D. Ritchie
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Matthew Palmer
- Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Todd L. Edwards
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Benjamin F. Voight
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Adriana M. Hung
- Division of Nephrology and Hypertension, Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- VA Tennessee Valley Healthcare System, Clinical Sciences Research and Development, Nashville, TN, USA
| | - Katalin Susztak
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Penn-CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA
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11
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Hill C, McKnight AJ, Smyth LJ. Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease. Diabet Med 2025; 42:e15447. [PMID: 39460977 PMCID: PMC11733670 DOI: 10.1111/dme.15447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
AIM Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. METHODS This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. RESULTS Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. CONCLUSION Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Amy Jayne McKnight
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Laura J. Smyth
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
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12
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Gorski M, Wiegrebe S, Burkhardt R, Behr M, Küchenhoff H, Stark KJ, Böger CA, Heid IM. Bias-corrected serum creatinine from UK Biobank electronic medical records generates an important data resource for kidney function trajectories. Sci Rep 2025; 15:3540. [PMID: 39875408 PMCID: PMC11775100 DOI: 10.1038/s41598-025-85391-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 01/02/2025] [Indexed: 01/30/2025] Open
Abstract
Loss of kidney function is a substantial personal and public health burden. Kidney function is typically assessed as estimated glomerular filtration rate (eGFR) based on serum creatinine. UK Biobank provides serum creatinine measurements from study center assessments (SC, n = 425,147 baseline, n = 15,314 with follow-up) and emerging electronic Medical Records (eMR, "GP-clinical") present a promising resource to augment this data longitudinally. However, it is unclear whether eMR-based and SC-based creatinine values can be used jointly for research on eGFR decline. When comparing eMR-based with SC-based creatinine by calendar year (n = 70,231), we found a year-specific multiplicative bias for eMR-based creatinine that decreased over time (factor 0.84 for 2007, 0.97 for 2013). Deriving eGFR based on SC- and bias-corrected eMR-creatinine yielded 454,907 individuals with ≥ 1eGFR assessment (2,102,174 assessments). This included 206,063 individuals with ≥ 2 assessments over up to 60.2 years (median 6.00 assessments, median time = 8.7 years), where we also obtained eMR-based information on kidney disease or renal replacement therapy. We found an annual eGFR decline of 0.11 (95%-CI = 0.10-0.12) versus 1.04 mL/min/1.73m2/year (95%-CI = 1.03-1.05) without and with bias-correction, the latter being in line with literature. In summary, our bias-corrected eMR-based creatinine values enabled a 4-fold increased number of eGFR assessments in UK Biobank suitable for kidney function research.
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Affiliation(s)
- Mathias Gorski
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
| | - Simon Wiegrebe
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
- Statistical Consulting Unit StaBLab, Department of Statistics, Ludwig-Maximilians-Universität, Munich, Germany
| | - Ralph Burkhardt
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Merle Behr
- Faculty of Informatics and Data Science, University of Regensburg, Regensburg, Germany
| | - Helmut Küchenhoff
- Statistical Consulting Unit StaBLab, Department of Statistics, Ludwig-Maximilians-Universität, Munich, Germany
- Munich Center for Machine Learning (MCML), Munich, Germany
| | - Klaus J Stark
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
| | - Carsten A Böger
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
- Department of Nephrology, Diabetology and Rheumatology, Kliniken Südostbayern, Traunstein, Germany
- KfH Kidney Center Traunstein, Traunstein, Germany
| | - Iris M Heid
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
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13
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Bazua-Valenti S, Brown MR, Zavras J, Riedl Khursigara M, Grinkevich E, Sidhom EH, Keller KH, Racette M, Dvela-Levitt M, Quintanova C, Demirci H, Sewerin S, Goss AC, Lin J, Yoo H, Vaca Jacome AS, Papanastasiou M, Udeshi N, Carr SA, Himmerkus N, Bleich M, Mutig K, Bachmann S, Halbritter J, Kmoch S, Živná M, Kidd K, Bleyer AJ, Weins A, Alper SL, Shaw JL, Kost-Alimova M, Pablo JLB, Greka A. Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors. J Clin Invest 2024; 134:e180347. [PMID: 39680459 PMCID: PMC11645142 DOI: 10.1172/jci180347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 10/22/2024] [Indexed: 12/18/2024] Open
Abstract
The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.
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Affiliation(s)
- Silvana Bazua-Valenti
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Departamento de Nefrología y Metabolismo Mineral, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - Matthew R. Brown
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Jason Zavras
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Magdalena Riedl Khursigara
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Elizabeth Grinkevich
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Eriene-Heidi Sidhom
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Keith H. Keller
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Matthew Racette
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Moran Dvela-Levitt
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | | | - Hasan Demirci
- Institute of Translational Physiology and
- Department of Anatomy, Charité - Universitätsmedizin, Berlin, Germany
| | - Sebastian Sewerin
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Alissa C. Goss
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - John Lin
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Hyery Yoo
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Alvaro S. Vaca Jacome
- Proteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Malvina Papanastasiou
- Proteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Namrata Udeshi
- Proteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Steven A. Carr
- Proteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Nina Himmerkus
- Institute of Physiology, Christian - Albrechts - Universität, Kiel, Germany
| | - Markus Bleich
- Institute of Physiology, Christian - Albrechts - Universität, Kiel, Germany
| | - Kerim Mutig
- Institute of Translational Physiology and
- Department of Anatomy, Charité - Universitätsmedizin, Berlin, Germany
| | - Sebastian Bachmann
- Institute of Translational Physiology and
- Department of Anatomy, Charité - Universitätsmedizin, Berlin, Germany
| | - Jan Halbritter
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin, Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stanislav Kmoch
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martina Živná
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kendrah Kidd
- Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina, USA
| | - Anthony J. Bleyer
- Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina, USA
| | - Astrid Weins
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Seth L. Alper
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Division of Nephrology, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jillian L. Shaw
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Maria Kost-Alimova
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Juan Lorenzo B. Pablo
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
| | - Anna Greka
- The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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14
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Nanamatsu A, de Araújo L, LaFavers KA, El-Achkar TM. Advances in uromodulin biology and potential clinical applications. Nat Rev Nephrol 2024; 20:806-821. [PMID: 39160319 PMCID: PMC11568936 DOI: 10.1038/s41581-024-00881-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/21/2024]
Abstract
Uromodulin (also known as Tamm-Horsfall protein) is a kidney-specific glycoprotein secreted bidirectionally into urine and into the circulation, and it is the most abundant protein in normal urine. Although the discovery of uromodulin predates modern medicine, its significance in health and disease has been rather enigmatic. Research studies have gradually revealed that uromodulin exists in multiple forms and has important roles in urinary and systemic homeostasis. Most uromodulin in urine is polymerized into highly organized filaments, whereas non-polymeric uromodulin is detected both in urine and in the circulation, and can have distinct roles. The interactions of uromodulin with the immune system, which were initially reported to be a key role of this protein, are now better understood. Moreover, the discovery that uromodulin is associated with a spectrum of kidney diseases, including acute kidney injury, chronic kidney disease and autosomal-dominant tubulointerstitial kidney disease, has further accelerated investigations into the role of this protein. These discoveries have prompted new questions and ushered in a new era in uromodulin research. Here, we delineate the latest discoveries in uromodulin biology and its emerging roles in modulating kidney and systemic diseases, and consider future directions, including its potential clinical applications.
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Affiliation(s)
- Azuma Nanamatsu
- Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Larissa de Araújo
- Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kaice A LaFavers
- Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tarek M El-Achkar
- Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Roudebush VA Medical Center, Indianapolis, IN, USA.
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15
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Strauss-Kruger M, Olinger E, Hofmann P, Wilson IJ, Mels C, Kruger R, Gafane-Matemane LF, Sayer JA, Ricci C, Schutte AE, Devuyst O. UMOD Genotype and Determinants of Urinary Uromodulin in African Populations. Kidney Int Rep 2024; 9:3477-3489. [PMID: 39698369 PMCID: PMC11652103 DOI: 10.1016/j.ekir.2024.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Single-nucleotide polymorphisms (SNPs) in the UMOD -PDILT genetic locus are associated with chronic kidney disease (CKD) in European populations, through their effect on urinary uromodulin (uUMOD) levels. The genetic and nongenetic factors associated with uUMOD in African populations remain unknown. Methods Clinical parameters, 3 selected UMOD-PDILT SNPs and uUMOD levels were obtained in 1202 young Black and White adults from the African-PREDICT study and 1943 middle aged Black adults from the PURE-NWP-SA study, 2 cross-sectional, observational studies. Results Absolute uUMOD and uUMOD/creatinine levels were lower in Black participants compared to White participants. The prime CKD-risk allele at rs12917707 was more prevalent in Black individuals, with strikingly more risk allele homozygotes compared to White individuals. Haplotype analysis of the UMOD-PDILT locus predicted more recombination events and linkage disequilibrium (LD) fragmentation in Black individuals. Multivariate testing and sensitivity analysis showed that higher uUMOD/creatinine associated specifically with risk alleles at rs12917707 and rs12446492 in White participants and with higher serum renin and lower urine albumin-to-creatinine ratio in Black participants, with a significant interaction of ethnicity on the relationship between all 3 SNPs and uUMOD/creatinine. The multiple regression model explained a greater percentage of the variance of uUMOD/creatinine in White adults compared to Black adults (23% vs. 8%). Conclusion We evidenced ethnic differences in clinical and genetic determinants of uUMOD levels, in particular an interaction of ethnicity on the relationship between CKD-risk SNPs and uUMOD. These differences should be considered when analyzing the role of uromodulin in kidney function, interpreting genome-wide association studies (GWAS), and precision medicine recommendations.
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Affiliation(s)
- Michél Strauss-Kruger
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa
| | - Eric Olinger
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Patrick Hofmann
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Ian J. Wilson
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Carina Mels
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa
| | - Ruan Kruger
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa
| | - Lebo F. Gafane-Matemane
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa
| | - John A. Sayer
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Cristian Ricci
- African Unit for Transdisciplinary Health Research, North-West University, Potchefstroom, North-West Province, South Africa
| | - Aletta E. Schutte
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa
- DSI-NRF Centre of Excellence in Human Development and SAMRC/Wits Developmental Pathways for Health Research Unit, University of the Witwatersrand, Johannesburg, South Africa
- The George Institute for Global Health, Sydney, New South Wales, Australia
- School of Population Health, University of New South Wales; Sydney, New South Wales, Australia
| | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Institute for Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Bondue T, Cervellini F, Smeets B, Strelkov SV, Horuz-Engels F, Veys K, Vargas-Poussou R, Matteis MAD, Staiano L, van den Heuvel L, Levtchenko E. CCDC158: A novel regulator in renal proximal tubular endocytosis unveiled through exome sequencing and interactome analysis. J Cell Physiol 2024; 239:e31447. [PMID: 39319391 DOI: 10.1002/jcp.31447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 08/29/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024]
Abstract
Renal proximal tubular reabsorption of proteins and polypeptides is tightly regulated by a concerted action of the multi-ligand receptors with subsequent processing from the clathrin-coated pits to early/recycling and late endosomes and towards lysosomes. We performed whole exome-sequencing in a male patient from a consanguineous family, who presented with low- and intermediate molecular weight proteinuria, nephrocalcinosis and oligospermia. We identified a new potential player in tubular endocytosis, coiled-coil domain containing 158 (CCDC158). The variant in CCDC158 segregated with the phenotype and was also detected in a female sibling with a similar clinical kidney phenotype. We demonstrated the expression of this protein in kidney tubules and modeled its structure in silico. We hypothesized that the protein played a role in the tubular endocytosis by interacting with other endocytosis regulators, and used mass spectrometry to identify potential interactors. The role of CCDC158 in receptor-mediated endocytosis was further confirmed by transferrin and GST-RAP trafficking analyses in patient-derived proximal tubular epithelial cells. Finally, as CCDC158 is known to be expressed in the testis, the presence of oligospermia in the male sibling further substantiated the pathogenic role of the detected missense variant in the observed phenotype. In this study, we provide data that demonstrate the potential role of CCDC158 in receptor-mediated endocytosis, most likely by interaction with other endocytosis-related proteins that strongly correlate with the proximal tubular dysfunction phenotype as observed in the patients. However, more studies are needed to fully unravel the molecular mechanism(s) in which CCDC158 is involved.
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Affiliation(s)
- Tjessa Bondue
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Francesca Cervellini
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Genomics and Experimental Medicine Program, Scuola Superiore Meridionale, Naples, Italy
| | - Bart Smeets
- Department of Pathology, Radboud University Medical Center, Radboud Institute of Molecular Life Science, Nijmegen, The Netherlands
| | - Sergei V Strelkov
- Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Flore Horuz-Engels
- Department of Pediatric Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Koenraad Veys
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Pediatrics, AZ Delta Campus, Torhout, Belgium
- Division of Pediatric Nephrology, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Rosa Vargas-Poussou
- Service de médecine génomique des maladies rares, AP-HP, Université Paris Cité, Paris, France
- Centre de référence des maladies rénales héréditaires de l'enfant et de l'adulte MARHEA, hôpital Necker-Enfants Malades, Paris, France
- CNRS, centre de recherche des Cordeliers, Inserm UMRS 1138, Sorbonne université, université Paris Cité, Paris, France
| | - Maria Antonietta De Matteis
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Leopoldo Staiano
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
| | - Lambertus van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Elena Levtchenko
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam, The Netherlands
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Smiles WJ, Ovens AJ, Oakhill JS, Kofler B. The metabolic sensor AMPK: Twelve enzymes in one. Mol Metab 2024; 90:102042. [PMID: 39362600 PMCID: PMC11752127 DOI: 10.1016/j.molmet.2024.102042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/12/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined. SCOPE OF REVIEW Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research. MAJOR CONCLUSIONS Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.
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Affiliation(s)
- William J Smiles
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia.
| | - Ashley J Ovens
- Protein Engineering in Immunity & Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
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Reghuvaran A, Kumar A, Lin Q, Rajeevan N, Sun Z, Shi H, Barsotti G, Tanvir EM, Pell J, Perincheri S, Wei C, Planoutene M, Eichmann A, Mas V, Zhang W, Das B, Cantley L, Xu L, He CJ, Menon MC. Shroom3-Rock interaction and profibrotic function: Resolving mechanism of an intronic CKD risk allele. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.22.624409. [PMID: 39605692 PMCID: PMC11601673 DOI: 10.1101/2024.11.22.624409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Common intronic enhancer SNPs in Shroom3 associate with CKD in GWAS, although there is paucity of detailed mechanism. Previously, we reported a role for Shroom3 in mediating crosstalk between TGFβ1- & Wnt/Ctnnb1 pathways promoting renal fibrosis (TIF). However, beneficial roles for Shroom3 in proteinuria have also been reported suggesting pleiotropic effects. Here we focused on identifying the specific profibrotic Shroom3 motif. Given known therapeutic roles for Rho-kinase inhibitors in experimental CKD, and the established interaction between Shroom3 and Rock via its ASD2 domain, we hypothesized that Shroom3-mediated ROCK activation played a crucial role in its profibrotic function in high expressors. To test this hypothesis, we developed transgenic mice and cell lines that inducibly overexpressed wild-type- (WT-Sh3) or ASD2-domain deletion- Shroom3 (ASD2Δ-Sh3). Prior scRNAseq data showed that during TIF, Shroom3 and Rock co-expression occurred in injured tubular cells and fibroblasts, highlighting cell-types where this mechanism could be involved. Using HEK293T cells, we first confirmed absent ROCK binding and inhibited TGFβ1-signaling with ASD2Δ-Sh3-overexpression vs WT-Sh3. In mIMCD cells, ASD2Δ-Sh3 overexpression, reduced Rock activation (phospho-MYPT1), pro-fibrotic and pro-inflammatory transcripts vs WT-Sh3. Fibroblast proliferation (3T3) was also reduced with ASD2Δ-Sh3. In vivo , we studied ureteric obstruction (UUO) and Aristolochic nephropathy (AAN) as TIF models. In AAN, inducible global-, or Pan-tubular specific-, WTSh3-overexpression showed increased azotemia, and TIF vs ASD2Δ-Sh3 mice. WT-Sh3 mice consistently showed significant enrichment of Rho-GTPase, TGFβ1- and Wnt/CtnnB1- signaling in kidney transcriptome, paralleling Shroom3-coexpressed genes in tubulo-interstitial transcriptomes from human CKD. In UUO, again WT-Sh3 mice recapitulated increased fibrosis vs ASD2Δ-Sh3. Importantly, ASD2Δ-Sh3 did not develop albuminuria vs WT-Sh3, while mutating a disparate Fyn-binding Shroom3 motif induced albuminuria in mice, suggesting motif-specific roles for Shroom3 in the kidney. Hence, our data show a critical role for the Rock-binding, ASD2-domain in mediating TIF in milieu of Shroom3 excess, with relevance to human CKD.
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Galuška D, Pácal L, Chalásová K, Divácká P, Řehořová J, Svojanovský J, Hubáček JA, Lánská V, Kaňková K. T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects. Gene 2024; 927:148724. [PMID: 38909968 DOI: 10.1016/j.gene.2024.148724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/14/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.
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Affiliation(s)
- David Galuška
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Biochemistry, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
| | - Lukáš Pácal
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Katarína Chalásová
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Petra Divácká
- Department of Gastroenterology, University Hospital Brno-Bohunice, Brno, Czech Republic
| | - Jitka Řehořová
- Department of Gastroenterology, University Hospital Brno-Bohunice, Brno, Czech Republic
| | - Jan Svojanovský
- Department of Internal Medicine, St. Anne's University Hospital, Brno, Czech Republic
| | - Jaroslav A Hubáček
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 3rd Department of Internal Medicine, 1(st) Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Věra Lánská
- Department of Data Science, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Kateřina Kaňková
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Kim S, Koppitch K, Parvez RK, Guo J, Achieng M, Schnell J, Lindström NO, McMahon AP. Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development. Dev Cell 2024; 59:2912-2930.e7. [PMID: 39121855 DOI: 10.1016/j.devcel.2024.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 04/02/2024] [Accepted: 07/12/2024] [Indexed: 08/12/2024]
Abstract
The mammalian kidney maintains fluid homeostasis through diverse epithelial cell types generated from nephron and ureteric progenitor cells. To extend a developmental understanding of the kidney's epithelial networks, we compared chromatin organization (single-nuclear assay for transposase-accessible chromatin sequencing [ATAC-seq]; 112,864 nuclei) and gene expression (single-cell/nuclear RNA sequencing [RNA-seq]; 109,477 cells/nuclei) in the developing human (10.6-17.6 weeks; n = 10) and mouse (post-natal day [P]0; n = 10) kidney, supplementing analysis with published mouse datasets from earlier stages. Single-cell/nuclear datasets were analyzed at a species level, and then nephron and ureteric cellular lineages were extracted and integrated into a common, cross-species, multimodal dataset. Comparative computational analyses identified conserved and divergent features of chromatin organization and linked gene activity, identifying species-specific and cell-type-specific regulatory programs. In situ validation of human-enriched gene activity points to human-specific signaling interactions in kidney development. Further, human-specific enhancer regions were linked to kidney diseases through genome-wide association studies (GWASs), highlighting the potential for clinical insight from developmental modeling.
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Affiliation(s)
- Sunghyun Kim
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Kari Koppitch
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Riana K Parvez
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Jinjin Guo
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - MaryAnne Achieng
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Jack Schnell
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Nils O Lindström
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Andrew P McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
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Jones AC, Patki A, Srinivasasainagendra V, Tiwari HK, Armstrong ND, Chaudhary NS, Limdi NA, Hidalgo BA, Davis B, Cimino JJ, Khan A, Kiryluk K, Lange LA, Lange EM, Arnett DK, Young BA, Diamantidis CJ, Franceschini N, Wassertheil-Smoller S, Rich SS, Rotter JI, Mychaleckyj JC, Kramer HJ, Chen YDI, Psaty BM, Brody JA, de Boer IH, Bansal N, Bis JC, Irvin MR. Single-Ancestry versus Multi-Ancestry Polygenic Risk Scores for CKD in Black American Populations. J Am Soc Nephrol 2024; 35:1558-1569. [PMID: 39073889 PMCID: PMC11543021 DOI: 10.1681/asn.0000000000000437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 06/28/2024] [Indexed: 07/31/2024] Open
Abstract
Key Points The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits. However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations. Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR. Background CKD is a risk factor of cardiovascular disease and early death. Recently, polygenic risk scores (PRSs) have been developed to quantify risk for CKD. However, African ancestry populations are underrepresented in both CKD genetic studies and PRS development overall. Moreover, European ancestry–derived PRSs demonstrate diminished predictive performance in African ancestry populations. Methods This study aimed to develop a PRS for CKD in Black American populations. We obtained score weights from a meta-analysis of genome-wide association studies for eGFR in the Million Veteran Program and Reasons for Geographic and Racial Differences in Stroke Study to develop an eGFR PRS. We optimized the PRS risk model in a cohort of participants from the Hypertension Genetic Epidemiology Network. Validation was performed in subsets of Black participants of the Trans-Omics in Precision Medicine Consortium and Genetics of Hypertension Associated Treatment Study. Results The prevalence of CKD—defined as stage 3 or higher—was associated with the PRS as a continuous predictor (odds ratio [95% confidence interval]: 1.35 [1.08 to 1.68]) and in a threshold-dependent manner. Furthermore, including APOL1 risk status—a putative variant for CKD with higher prevalence among those of sub-Saharan African descent—improved the score's accuracy. PRS associations were robust to sensitivity analyses accounting for traditional CKD risk factors, as well as CKD classification based on prior eGFR equations. Compared with previously published PRS, the predictive performance of our PRS was comparable with a European ancestry–derived PRS for kidney traits. However, single-ancestry PRSs were less predictive than multi-ancestry–derived PRSs. Conclusions In this study, we developed a PRS that was significantly associated with CKD with improved predictive accuracy when including APOL1 risk status. However, PRS generated from multi-ancestry populations outperformed single-ancestry PRS in our study.
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Affiliation(s)
- Alana C. Jones
- Medical Scientist Training Program, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Amit Patki
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Vinodh Srinivasasainagendra
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Hemant K. Tiwari
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nicole D. Armstrong
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ninad S. Chaudhary
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nita A. Limdi
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Bertha A. Hidalgo
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Brittney Davis
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - James J. Cimino
- Department of Biomedical Informatics and Data Science, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Atlas Khan
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York
| | - Leslie A. Lange
- Department of Biomedical Informatics, University of Colorado-Anschutz, Aurora, Colorado
| | - Ethan M. Lange
- Department of Biomedical Informatics, University of Colorado-Anschutz, Aurora, Colorado
| | - Donna K. Arnett
- Office of the Provost, University of South Carolina, Columbia, South Carolina
| | - Bessie A. Young
- Division of Nephrology, University of Washington, Seattle, Washington
| | | | - Nora Franceschini
- Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Sylvia Wassertheil-Smoller
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York
| | - Stephen S. Rich
- Department of Genome Sciences, University of Virginia, Charlottesville, Virginia
| | - Jerome I. Rotter
- Department of Pediatrics, The Institute for Translational Genomic and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbort-UCLA Medical Center, Torrance, California
| | - Josyf C. Mychaleckyj
- Department of Genome Sciences, University of Virginia, Charlottesville, Virginia
| | - Holly J. Kramer
- Departments of Public Health Sciences and Medicine, Loyola University Medical Center, Taywood, Illinois
| | - Yii-Der I. Chen
- Department of Pediatrics, The Institute for Translational Genomic and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbort-UCLA Medical Center, Torrance, California
| | - Bruce M. Psaty
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Ian H. de Boer
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Nisha Bansal
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Marguerite R. Irvin
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
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Feng H, Yu J, Xu Z, Sang Q, Li F, Chen M, Chen Y, Yu B, Zhu N, Xia J, He C, Hou J, Wu X, Yan C, Zhu Z, Su L, Li J, Dai W, Li YY, Liu B. SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer. EBioMedicine 2024; 109:105375. [PMID: 39437660 PMCID: PMC11536348 DOI: 10.1016/j.ebiom.2024.105375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis. METHODS Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown. FINDINGS Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown. INTERPRETATION SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53. FUNDING This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.
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Affiliation(s)
- Haoran Feng
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Junxian Yu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhuoqing Xu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qingqing Sang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Fangyuan Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Mengdi Chen
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yunqin Chen
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200080, China
| | - Beiqin Yu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Nan Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiazeng Xia
- Department of General Surgery, Jiangnan University Medical Center, Wuxi 200240, China
| | - Changyu He
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Junyi Hou
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiongyan Wu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chao Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhenggang Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Liping Su
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jianfang Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wentao Dai
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200080, China.
| | - Yuan-Yuan Li
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200080, China.
| | - Bingya Liu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Zhao P, Li Z, Xue S, Cui J, Zhan Y, Zhu Z, Zhang X. Proteome-wide mendelian randomization identifies novel therapeutic targets for chronic kidney disease. Sci Rep 2024; 14:22114. [PMID: 39333727 PMCID: PMC11437114 DOI: 10.1038/s41598-024-72970-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 09/12/2024] [Indexed: 09/29/2024] Open
Abstract
There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR.
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Affiliation(s)
- Pin Zhao
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China
| | - Zhenhao Li
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China
| | - Shilong Xue
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China
| | - Jinshan Cui
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China
| | - Yonghao Zhan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China
| | - Zhaowei Zhu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China.
| | - Xuepei Zhang
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China.
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Jaykumar AB, Monu SR, Mendez M, Rhaleb NE, Ortiz PA. ALMS1 KO rat: a new model of metabolic syndrome with spontaneous hypertension. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.22.614364. [PMID: 39386593 PMCID: PMC11463523 DOI: 10.1101/2024.09.22.614364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
ALMS1 is a protein initially associated with Alström syndrome. This is a rare human disorder characterized by metabolic dysfunction, hypertension, obesity and hyperinsulinemia. In addition, ALMS1 gene was linked to hypertension status in a multipoint linkage population analysis. However, the mechanisms by which ALMS1 contributes to the development of obesity, insulin resistance and other metabolic disturbances are unknown. To study the role of ALMS1 in blood pressure regulation and renal function we previously generated an ALMS1 knockout rat model, where we found these rats are hypertensive. In this study, we further characterized the ALMS1 knockout rat, and found that they exhibit most characteristics of metabolic syndrome including hypertension and higher body weight by 10-12 weeks of age. In contrast, obesity, hyperinsulinemia and vascular dysfunction manifested at around 14-16 weeks of age. Interestingly, ALMS1 KO rats developed hyperleptinemia prior to the development of obesity rapidly after weaning by 7 weeks of age, suggesting an early role for ALMS1 in the hormonal control of leptin. We also found that female ALMS1 KO rats develop severe metabolic syndrome with hypertension similar to their male counterparts, lacking any protection often associated with better cardiovascular outcomes. Therefore, ALMS1 is an essential gene for sex- and age-dependent metabolic function. The ALMS1 knockout rat provides an invaluable pre-clinical animal model that recapitulates most symptoms present in patients and allows the study of new drugs and mechanisms that cause metabolic syndrome.
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Affiliation(s)
- Ankita B. Jaykumar
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, USA
- Department of Physiology, Wayne State School of Medicine, Detroit, USA
| | - Sumit R. Monu
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, USA
- Department of Physiology, Wayne State School of Medicine, Detroit, USA
| | - Mariela Mendez
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, USA
- Department of Physiology, Wayne State School of Medicine, Detroit, USA
| | - Nour-Eddine Rhaleb
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, USA
- Department of Physiology, Wayne State School of Medicine, Detroit, USA
| | - Pablo A. Ortiz
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, USA
- Department of Physiology, Wayne State School of Medicine, Detroit, USA
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Cañadas-Garre M, Maqueda JJ, Baños-Jaime B, Hill C, Skelly R, Cappa R, Brennan E, Doyle R, Godson C, Maxwell AP, McKnight AJ. Mitochondrial related variants associated with cardiovascular traits. Front Physiol 2024; 15:1395371. [PMID: 39258111 PMCID: PMC11385366 DOI: 10.3389/fphys.2024.1395371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
Introduction Cardiovascular disease (CVD) is responsible for over 30% of mortality worldwide. CVD arises from the complex influence of molecular, clinical, social, and environmental factors. Despite the growing number of autosomal genetic variants contributing to CVD, the cause of most CVDs is still unclear. Mitochondria are crucial in the pathophysiology, development and progression of CVDs; the impact of mitochondrial DNA (mtDNA) variants and mitochondrial haplogroups in the context of CVD has recently been highlighted. Aims We investigated the role of genetic variants in both mtDNA and nuclear-encoded mitochondrial genes (NEMG) in CVD, including coronary artery disease (CAD), hypertension, and serum lipids in the UK Biobank, with sub-group analysis for diabetes. Methods We investigated 371,542 variants in 2,527 NEMG, along with 192 variants in 32 mitochondrial genes in 381,994 participants of the UK Biobank, stratifying by presence of diabetes. Results Mitochondrial variants showed associations with CVD, hypertension, and serum lipids. Mitochondrial haplogroup J was associated with CAD and serum lipids, whereas mitochondrial haplogroups T and U were associated with CVD. Among NEMG, variants within Nitric Oxide Synthase 3 (NOS3) showed associations with CVD, CAD, hypertension, as well as diastolic and systolic blood pressure. We also identified Translocase Of Outer Mitochondrial Membrane 40 (TOMM40) variants associated with CAD; Solute carrier family 22 member 2 (SLC22A2) variants associated with CAD and CVD; and HLA-DQA1 variants associated with hypertension. Variants within these three genes were also associated with serum lipids. Conclusion Our study demonstrates the relevance of mitochondrial related variants in the context of CVD. We have linked mitochondrial haplogroup U to CVD, confirmed association of mitochondrial haplogroups J and T with CVD and proposed new markers of hypertension and serum lipids in the context of diabetes. We have also evidenced connections between the etiological pathways underlying CVDs, blood pressure and serum lipids, placing NOS3, SLC22A2, TOMM40 and HLA-DQA1 genes as common nexuses.
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Affiliation(s)
- Marisa Cañadas-Garre
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol Oakfield House, Belfast, United Kingdom
| | - Joaquín J Maqueda
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Blanca Baños-Jaime
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain
| | - Claire Hill
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
| | - Ryan Skelly
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
| | - Ruaidhri Cappa
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
| | - Eoin Brennan
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Ross Doyle
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Alexander P Maxwell
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
- Regional Nephrology Unit, Belfast City Hospital Belfast, Belfast, United Kingdom
| | - Amy Jayne McKnight
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, United Kingdom
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Jang MJ, Tan LJ, Park MY, Shin S, Kim JM. Identification of interactions between genetic risk scores and dietary patterns for personalized prevention of kidney dysfunction in a population-based cohort. Nutr Diabetes 2024; 14:62. [PMID: 39143076 PMCID: PMC11325018 DOI: 10.1038/s41387-024-00316-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 07/09/2024] [Accepted: 07/16/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND & AIM Chronic kidney disease (CKD) is a heterogeneous disorder that affects the kidney structure and function. This study investigated the effect of the interaction between genetic factors and dietary pattern on kidney dysfunction in Korean adults. METHODS Baseline data were obtained from the Ansan and Ansung Study of the Korean Genome and Epidemiology Study involving 8230 participants aged 40-69 years. Kidney dysfunction was defined as an estimated glomerular filtration rate < 90 mL/minute/1.73 m2. Genomic DNAs genotyped on the Affymetrix® Genome-Wide Human SNP array 5.0 were isolated from peripheral blood. A genome-wide association study using a generalized linear model was performed on 1,590,162 single-nucleotide polymorphisms (SNPs). To select significant SNPs, the threshold criterion was set at P-value < 5 × 10-8. Linkage disequilibrium clumping was performed based on the R2 value, and 94 SNPs had a significant effect. Participants were divided into two groups based on their generic risk score (GRS): the low-GR group had GRS > 0, while the high-GR group had GRS ≤ 0. RESULTS Three distinct dietary patterns were extracted, namely, the "prudent pattern," "flour-based and animal food pattern," and "white rice pattern," to analyze the effect of dietary pattern on kidney function. In the "flour-based and animal food pattern," higher pattern scores were associated with a higher prevalence of kidney dysfunction in both the low and high GR groups (P for trend < 0.0001 in the low-, high-GR groups of model 1; 0.0050 and 0.0065 in the low-, high-GR groups of model 2, respectively). CONCLUSIONS The results highlight a significant association between the 'flour-based and animal food pattern' and higher kidney dysfunction prevalence in individuals with both low and high GR. These findings suggest that personalized nutritional interventions based on GR profiles may become the basis for presenting GR-based individual dietary patterns for kidney dysfunction.
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Affiliation(s)
- Min-Jae Jang
- Department of Animal Science and Technology, Chung-Ang University, Gyeonggi-do, 17546, Korea
| | - Li-Juan Tan
- Department of Food and Nutrition, Chung-Ang University, Gyeonggi-do, 17546, Korea
| | - Min Young Park
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, USA
| | - Sangah Shin
- Department of Food and Nutrition, Chung-Ang University, Gyeonggi-do, 17546, Korea.
| | - Jun-Mo Kim
- Department of Animal Science and Technology, Chung-Ang University, Gyeonggi-do, 17546, Korea.
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Chen Z, Xu LL, Du W, Ouyang Y, Gu X, Fang Z, Yu X, Li J, Xie L, Jin Y, Ma J, Wang Z, Pan X, Zhang W, Ren H, Wang W, Chen X, Zhou XJ, Zhang H, Chen N, Xie J. Uromodulin and progression of IgA nephropathy. Clin Kidney J 2024; 17:sfae209. [PMID: 39145144 PMCID: PMC11322676 DOI: 10.1093/ckj/sfae209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. METHODS We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. RESULTS The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. CONCLUSION The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.
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Affiliation(s)
- Zijin Chen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin-lin Xu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
| | - Wen Du
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Ouyang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangchen Gu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengying Fang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xialian Yu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junru Li
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Xie
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanmeng Jin
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Ma
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaohui Wang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxia Pan
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Zhang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Ren
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiming Wang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaonong Chen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu-jie Zhou
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
| | - Nan Chen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyuan Xie
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Tan SS, Tan WY, Zheng LS, Adinugraha P, Wang HY, Kumar S, Gulati A, Khurana S, Lam W, Aye T. Multi-year population-based analysis of Asian patients with acute decompensated heart failure and advanced chronic kidney disease. Curr Probl Cardiol 2024; 49:102618. [PMID: 38735349 DOI: 10.1016/j.cpcardiol.2024.102618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 05/05/2024] [Indexed: 05/14/2024]
Abstract
BACKGROUND Data on disparities in outcomes and risk factors in Asian patients with advanced chronic kidney disease admitted for heart failure are scare. METHODS This was a retrospective cohort study that utilized data from the National Inpatient Sample between January 2016 and December 2019. Patients who had a primary diagnosis of acute decompensated heart failure and a concomitant diagnosis of advanced CKD were included. The primary outcome of interest was in-hospital mortality. Secondary outcomes include hospital cost, length of stay, and other clinical outcomes. Weighted multivariable logistic regression was used to adjust for comorbidities. RESULTS There were 251,578 cases of ADHF with advanced CKD, out of which 2.6 % were from individuals of Asian ethnicity. Asian patients exhibited a higher burden of comorbidities in comparison to other UREM patients, but a lower burden than White patients. Regardless of differences in comorbidity burden, Asian patients exhibited a higher likelihood of experiencing severe consequences. After adjusting for comorbidies, White (OR:1.11; 95 % CI 1.03-1.20;0.009) patients had higher odds of mortality than Asian patients. However, Blacks (OR: 0.58; 95 % CI 0.53 to 0.63; p < 0.001) and Hispanics (OR: 0.69; 95 % CI 0.62 to 0.78; p < 0.001) had lower odds of mortality. CONCLUSION This first population-based studies shows that Asian patients with advanced CKD admitted for ADHF have greater comorbidity burden and poorer outcomes Black and Hispanic patients. This data underscores the importance of comprehensive approaches in phenotyping, and ethnic specific interventions.
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Affiliation(s)
- Samuel S Tan
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Beth Israel, New York, New York, USA.
| | - Wenchy Yy Tan
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Beth Israel, New York, New York, USA; Department of Population Health Sciences, Weill Cornell, New York, New York, USA
| | - Lucy S Zheng
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Beth Israel, New York, New York, USA
| | - Paulus Adinugraha
- Department of Cardiology, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel/West, New York, New York, USA
| | - Hong Yu Wang
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Beth Israel, New York, New York, USA
| | - Shasawat Kumar
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Beth Israel, New York, New York, USA
| | - Amit Gulati
- Department of Cardiology, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel/West, New York, New York, USA
| | - Sakshi Khurana
- Department of Radiology, Columbia University, New York, New York, USA
| | - Wan Lam
- Department of Medicine, Lenox Hill Hospital, New York, New York, USA
| | - Thida Aye
- Department of Medicine, Lenox Hill Hospital, New York, New York, USA
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Karagiannidis AG, Theodorakopoulou MP, Pella E, Sarafidis PA, Ortiz A. Uromodulin biology. Nephrol Dial Transplant 2024; 39:1073-1087. [PMID: 38211973 PMCID: PMC11210992 DOI: 10.1093/ndt/gfae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Indexed: 01/13/2024] Open
Abstract
Uromodulin is a kidney-specific glycoprotein which is exclusively produced by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. It is currently recognized as a multifaceted player in kidney physiology and disease, with discrete roles for intracellular, urinary, interstitial and serum uromodulin. Among these, uromodulin modulates renal sodium handling through the regulation of tubular sodium transporters that reabsorb sodium and are targeted by diuretics, such as the loop diuretic-sensitive Na+-K+-2Cl- cotransporter type 2 (NKCC2) and the thiazide-sensitive Na+/Cl- cotransporter (NCC). Given these roles, the contribution of uromodulin to sodium-sensitive hypertension has been proposed. However, recent studies in humans suggest a more complex interaction between dietary sodium intake, uromodulin and blood pressure. This review presents an updated overview of the uromodulin's biology and its various roles, and focuses on the interaction between uromodulin and sodium-sensitive hypertension.
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Affiliation(s)
- Artemios G Karagiannidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta P Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eva Pella
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis A Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
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Cañadas-Garre M, Baños-Jaime B, Maqueda JJ, Smyth LJ, Cappa R, Skelly R, Hill C, Brennan EP, Doyle R, Godson C, Maxwell AP, McKnight AJ. Genetic variants affecting mitochondrial function provide further insights for kidney disease. BMC Genomics 2024; 25:576. [PMID: 38858654 PMCID: PMC11163707 DOI: 10.1186/s12864-024-10449-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 05/24/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. METHODS We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. RESULTS Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. CONCLUSIONS We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.
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Affiliation(s)
- Marisa Cañadas-Garre
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK.
- Genomic Oncology Area, Centre for Genomics and Oncological Research: Pfizer, GENYO, University of Granada-Andalusian Regional Government, PTS Granada. Avenida de La Ilustración 114, 18016, Granada, Spain.
- Hematology Department, Hospital Universitario Virgen de Las Nieves, Avenida de Las Fuerzas Armadas 2, 18014, Granada, Spain.
- Instituto de Investigación Biosanitaria de Granada (Ibs.GRANADA), Avda. de Madrid, 15, 18012, Granada, Spain.
| | - Blanca Baños-Jaime
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de La Cartuja (cicCartuja), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, Avda. Américo Vespucio 49, 41092, Seville, Spain
| | - Joaquín J Maqueda
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
- Experimental Oncology Laboratory, IRCCS Rizzoli Orthopaedic Institute, 40136, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126, Bologna, Italy
| | - Laura J Smyth
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
| | - Ruaidhri Cappa
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
| | - Ryan Skelly
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
| | - Claire Hill
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
| | - Eoin P Brennan
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, D04 V1W8, Ireland
- School of Medicine, University College Dublin, Dublin, D04 V1W8, Ireland
| | - Ross Doyle
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, D04 V1W8, Ireland
- School of Medicine, University College Dublin, Dublin, D04 V1W8, Ireland
- Mater Misericordiae University Hospital, Eccles St, Dublin, D07 R2WY, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, D04 V1W8, Ireland
- School of Medicine, University College Dublin, Dublin, D04 V1W8, Ireland
| | - Alexander P Maxwell
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
- Regional Nephrology Unit, Belfast City Hospital, Level 11Lisburn Road, Belfast, BT9 7AB, UK
| | - Amy Jayne McKnight
- Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK
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31
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Lin J, Li B, Xu Q, Liu YS, Kang YL, Wang X, Wang Y, Lei Y, Bai YL, Li XM, Zhou J. DACH1 attenuated PA-induced renal tubular injury through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway. J Endocrinol Invest 2024; 47:1531-1544. [PMID: 38147289 DOI: 10.1007/s40618-023-02253-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/20/2023] [Indexed: 12/27/2023]
Abstract
BACKGROUND Palmitic acid (PA), the major saturated fatty acid in the blood, often induces the initiation and progression of diabetic kidney disease (DKD). However, the underlying mechanism remains unclear. DACH1 is an important regulator of kidney functions. Herein, we investigated the roles of DACH1 in PA-induced kidney injury. METHODS Clinical data from the NHANES database were subjected to analyse the association between serum PA (sPA), blood glucose and kidney function. Molecular docking of PA was performed with DACH1. Immunohistochemistry, cell viability, annexin V/7-AAD double staining, TUNEL assay, immunofluorescent staining, autophagic flux analysis, qRT-PCR and western blot were performed. RESULTS Clinical data confirmed that sPA was increased significantly in the pathoglycemia individuals compared with controls and correlated negatively with renal function. Our findings suggested that PA could dock with DACH1. DACH1 enhances cell viability by inhibiting apoptosis and attenuating autophagy blockage induced by PA. Furthermore, the results demonstrated that DACH1 ameliorated inflammation and fibrosis through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway in PA-treated renal tubular epithelial cell line (HK-2). CONCLUSIONS This study proved that sPA presents a risk factor for kidney injuries and DACH1 might serve as a protective target against renal function deterioration in diabetic patients.
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Affiliation(s)
- J Lin
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - B Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Q Xu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y S Liu
- Department of Pharmacology, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medical of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Air Force Medical University, Xi'an, 710032, China
| | - Y L Kang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi'an, 710032, China
| | - X Wang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y Wang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y Lei
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712099, China
| | - Y L Bai
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi'an, 710032, China.
| | - X M Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China.
| | - J Zhou
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China.
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32
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Tanaka K, Hayasaka H, Matsusaka T. Dach1 is essential for maintaining normal mature podocytes. PLoS One 2024; 19:e0303910. [PMID: 38805434 PMCID: PMC11132487 DOI: 10.1371/journal.pone.0303910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/03/2024] [Indexed: 05/30/2024] Open
Abstract
Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we analyzed global, podocyte-specific, and inducible Dach1 knockout mice. Global Dach1 knockout (Dach1-/-) mice were assessed immediately after birth because they die within a day. The kidneys of Dach1-/- mice were slightly smaller than those of control mice but maintained a normal structure and normal podocyte phenotypes, including ultrastructure. To study the role of Dach1 in mature podocytes, we generated Dach1 knockout mice by mating Dach1fl/fl mice with Nphs1-Cre or ROSA-CreERT2 mice. Due to inefficient Cre recombination, only a small number of podocytes lacked Dach1 staining in these mice. However, all eleven Nphs1-Cre/Dach1fl/fl mice displayed abnormal albuminuria, and seven (63%) of them developed focal segmental glomerulosclerosis. Among 13 ROSA-CreERT2/Dach1fl/fl mice, eight (61%) exhibited abnormal albuminuria after treatment with tamoxifen, and five (38%) developed early sclerotic lesions. These results indicate that while Dach1 does not determine the fate of differentiation into podocytes, it is indispensable for maintaining the normal integrity of mature podocytes.
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Affiliation(s)
- Keiko Tanaka
- Departments of Physiology, Tokai University School of Medicine, Kanagawa, Japan
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Haruko Hayasaka
- Department of Science, Faculty of Science & Engineering, Graduate School of Science and Engineering, Kindai University, Osaka, Japan
| | - Taiji Matsusaka
- Departments of Physiology, Tokai University School of Medicine, Kanagawa, Japan
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Möckel T, Boegel S, Schwarting A. Transcriptome Analysis of BAFF/BAFF-R System in Murine Nephrotoxic Serum Nephritis. Int J Mol Sci 2024; 25:5415. [PMID: 38791453 PMCID: PMC11121395 DOI: 10.3390/ijms25105415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.
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Affiliation(s)
- Tamara Möckel
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (T.M.); (S.B.)
| | - Sebastian Boegel
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (T.M.); (S.B.)
| | - Andreas Schwarting
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (T.M.); (S.B.)
- Center for Rheumatic Disease Rhineland-Palatinate GmbH, 55543 Bad Kreuznach, Germany
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Osborne AJ, Bierzynska A, Colby E, Andag U, Kalra PA, Radresa O, Skroblin P, Taal MW, Welsh GI, Saleem MA, Campbell C. Multivariate canonical correlation analysis identifies additional genetic variants for chronic kidney disease. NPJ Syst Biol Appl 2024; 10:28. [PMID: 38459044 PMCID: PMC10924093 DOI: 10.1038/s41540-024-00350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/20/2024] [Indexed: 03/10/2024] Open
Abstract
Chronic kidney diseases (CKD) have genetic associations with kidney function. Univariate genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN), two complementary kidney function markers. However, it is unknown whether additional SNPs for kidney function can be identified by multivariate statistical analysis. To address this, we applied canonical correlation analysis (CCA), a multivariate method, to two individual-level CKD genotype datasets, and metaCCA to two published GWAS summary statistics datasets. We identified SNPs previously associated with kidney function by published univariate GWASs with high replication rates, validating the metaCCA method. We then extended discovery and identified previously unreported lead SNPs for both kidney function markers, jointly. These showed expression quantitative trait loci (eQTL) colocalisation with genes having significant differential expression between CKD and healthy individuals. Several of these identified lead missense SNPs were predicted to have a functional impact, including in SLC14A2. We also identified previously unreported lead SNPs that showed significant correlation with both kidney function markers, jointly, in the European ancestry CKDGen, National Unified Renal Translational Research Enterprise (NURTuRE)-CKD and Salford Kidney Study (SKS) datasets. Of these, rs3094060 colocalised with FLOT1 gene expression and was significantly more common in CKD cases in both NURTURE-CKD and SKS, than in the general population. Overall, by using multivariate analysis by CCA, we identified additional SNPs and genes for both kidney function and CKD, that can be prioritised for further CKD analyses.
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Affiliation(s)
- Amy J Osborne
- Intelligent Systems Laboratory, University of Bristol, Bristol, BS8 1TW, UK.
| | - Agnieszka Bierzynska
- Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, BS1 3NY, UK
| | - Elizabeth Colby
- Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, BS1 3NY, UK
| | - Uwe Andag
- Department of Metabolic and Renal Diseases, Evotec International GmbH, Marie-Curie-Strasse 7, 37079, Göttingen, Germany
| | - Philip A Kalra
- Department of Renal Medicine, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK
| | - Olivier Radresa
- Department of Metabolic and Renal Diseases, Evotec International GmbH, Marie-Curie-Strasse 7, 37079, Göttingen, Germany
| | - Philipp Skroblin
- Department of Metabolic and Renal Diseases, Evotec International GmbH, Marie-Curie-Strasse 7, 37079, Göttingen, Germany
| | - Maarten W Taal
- Centre for Kidney Research and Innovation, University of Nottingham, Derby, UK
| | - Gavin I Welsh
- Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, BS1 3NY, UK
| | - Moin A Saleem
- Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, BS1 3NY, UK
| | - Colin Campbell
- Intelligent Systems Laboratory, University of Bristol, Bristol, BS8 1TW, UK.
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Fountoglou A, Deltas C, Siomou E, Dounousi E. Genome-wide association studies reconstructing chronic kidney disease. Nephrol Dial Transplant 2024; 39:395-402. [PMID: 38124660 PMCID: PMC10899781 DOI: 10.1093/ndt/gfad209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Indexed: 12/23/2023] Open
Abstract
Chronic kidney disease (CKD) is a major health problem with an increasing epidemiological burden, and is the 16th leading cause of years of life lost worldwide. It is estimated that more than 10% of the population have a variable stage of CKD, while about 850 million people worldwide are affected. Nevertheless, public awareness remains low, clinical access is inappropriate in many circumstances and medication is still ineffective due to the lack of clear therapeutic targets. One of the main issues that drives these problems is the fact that CKD remains a clinical entity with significant causal ambiguity. Beyond diabetes mellitus and hypertension, which are the two major causes of kidney disease, there are still many gray areas in the diagnostic context of CKD. Genetics nowadays emerges as a promising field in nephrology. The role of genetic factors in CKD's causes and predisposition is well documented and thousands of genetic variants are well established to contribute to the high burden of disease. Next-generation sequencing is increasingly revealing old and new rare variants that cause Mendelian forms of chronic nephropathy while genome-wide association studies (GWAS) uncover common variants associated with CKD-defining traits in the general population. In this article we review how GWAS has revolutionized-and continues to revolutionize-the old concept of CKD. Furthermore, we present how the investigation of common genetic variants with previously unknown kidney significance has begun to expand our knowledge on disease understanding, providing valuable insights into disease mechanisms and perhaps paving the way for novel therapeutic targets.
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Affiliation(s)
- Anastasios Fountoglou
- Department of Nephrology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Constantinos Deltas
- School of Medicine and biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus
| | - Ekaterini Siomou
- Department of Pediatrics, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Evangelia Dounousi
- Department of Nephrology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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36
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Kim MJ, Jin HS, Eom YB. Coffee consumption affects kidney function based on GCKR polymorphism in a Korean population. Nutr Res 2024; 122:92-100. [PMID: 38215572 DOI: 10.1016/j.nutres.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 01/14/2024]
Abstract
Kidney function can be preserved through pharmacological interventions and nonpharmacological strategies, such as lifestyle and dietary adjustments. Among these, coffee has been linked to protective effects on kidney function. However, few studies have investigated the effect of coffee consumption on kidney function according to specific genes. We hypothesized that the impact of coffee consumption on kidney function might vary depending on GCKR polymorphism. GCKR rs1260326 polymorphism was examined using the Korean genome and epidemiology data from 656 chronic kidney disease (CKD) cases and 38,540 individuals without CKD (non-CKD). GCKR polymorphism has been previously associated with both coffee consumption and kidney function in Europeans. We replicated the associations between GCKR rs1260326 and coffee consumption and kidney function in Korean individuals. We also explored the effect of coffee consumption on kidney function by multivariate logistic regression analysis. Individuals with the rs1260326 (TC/CC) genotype did not experience significant changes in CKD risk based on their coffee consumption habits. In contrast, individuals with the TT genotype exhibited a significantly lower risk of CKD based on coffee consumption. Interestingly, in the non-CKD group, a beneficial effect on estimated glomerular filtration rate was observed in individuals with the T allele as coffee consumption increased. Our findings supported the hypothesis and revealed that the impact of coffee consumption habits on kidney function may vary based on the GCKR rs1260326 genotype of Korean individuals.
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Affiliation(s)
- Min-Jeong Kim
- Department of Medical Sciences, Graduate School, Soonchunhyang University, Asan, Chungnam 31538, Republic of Korea
| | - Hyun-Seok Jin
- Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Republic of Korea
| | - Yong-Bin Eom
- Department of Medical Sciences, Graduate School, Soonchunhyang University, Asan, Chungnam 31538, Republic of Korea; Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan, Chungnam 31538, Republic of Korea.
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37
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Singh C, Jin B, Shrestha N, Markhard AL, Panda A, Calvo SE, Deik A, Pan X, Zuckerman AL, Ben Saad A, Corey KE, Sjoquist J, Osganian S, AminiTabrizi R, Rhee EP, Shah H, Goldberger O, Mullen AC, Cracan V, Clish CB, Mootha VK, Goodman RP. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits. Cell Metab 2024; 36:144-158.e7. [PMID: 38101397 PMCID: PMC10842884 DOI: 10.1016/j.cmet.2023.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 07/24/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
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Affiliation(s)
- Charandeep Singh
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Byungchang Jin
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Nirajan Shrestha
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Andrew L Markhard
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Apekshya Panda
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Sarah E Calvo
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Amy Deik
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Xingxiu Pan
- The Scintillon Institute, San Diego, CA 92121, USA
| | - Austin L Zuckerman
- The Scintillon Institute, San Diego, CA 92121, USA; Program in Mathematics and Science Education, University of California, San Diego, La Jolla, CA 92093; Program in Mathematics and Science Education, San Diego State University, San Diego, CA 92120
| | - Amel Ben Saad
- Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Kathleen E Corey
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Julia Sjoquist
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Stephanie Osganian
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Roya AminiTabrizi
- Metabolomics Platform, Comprehensive Cancer Center, the University of Chicago, Chicago, IL 60637, USA
| | - Eugene P Rhee
- Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Hardik Shah
- Metabolomics Platform, Comprehensive Cancer Center, the University of Chicago, Chicago, IL 60637, USA
| | - Olga Goldberger
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Alan C Mullen
- Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Valentin Cracan
- The Scintillon Institute, San Diego, CA 92121, USA; Department of Chemistry, the Scripps Research Institute, La Jolla, CA 92037, USA
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Vamsi K Mootha
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Russell P Goodman
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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Sun G, Liu C, Song C, Geng X, Chi K, Fu Z, Hong Q, Wu D. Knowledge mapping of UMOD of English published work from 1985 to 2022: a bibliometric analysis. Int Urol Nephrol 2024; 56:249-261. [PMID: 37322316 PMCID: PMC10776727 DOI: 10.1007/s11255-023-03664-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND UMOD is exclusively produced by renal epithelial cells. Recent genome-wide association studies (GWAS) suggested that common variants in UMOD gene are closely connected with the risk of CKD. However, a comprehensive and objective report on the current status of UMOD research is lacking. Therefore, we aim to conduct a bibliometric analysis to quantify and identify the status quo and trending issues of UMOD research in the past. METHODS We collected data from the Web of Science Core Collection database and used the Online Analysis Platform of Literature Metrology, the Online Analysis Platform of Literature Metrology and Microsoft Excel 2019 to perform bibliometricanalysis and visualization. RESULTS Based on the data from the WoSCC database from 1985 to 2022, a total of 353 UMOD articles were published in 193 academic journals by 2346 authors from 50 different countries/regions and 396 institutions. The United States published the most papers. Professor Devuyst O from University of Zurich not only published the greatest number of UMOD-related papers but also is among the top 10 co-cited authors. KIDNEY INTERNATIONAL published the most necroptosis studies, and it was also the most cited journal. High-frequency keywords mainly included 'chronic kidney disease', 'Tamm Horsfall protein' and 'mutation'. CONCLUSIONS The number of UMOD-related articles has steadily increased over the past decades Current UMOD studies focused on Biological relevance of the UMOD to kidney function and potential applications in the risk of CKD mechanisms, these might provide ideas for further research in the UMOD field.
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Affiliation(s)
- Guannan Sun
- Medical School of Chinese PLA, Beijing, 100853, China
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Chao Liu
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Chengcheng Song
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Xiaodong Geng
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Kun Chi
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Zhangning Fu
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Quan Hong
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China
| | - Di Wu
- Medical School of Chinese PLA, Beijing, 100853, China.
- State Key Laboratory of Kidney Diseases, Department of Nephrology, First Medical Center of Chinese, National Clinical Research Center for Kidney Diseases, PLA General Hospital, Beijing, 100853, China.
- Department of Nephrology, Beijing Electric Power Hospital, Beijing, 100073, China.
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Abstract
Inorganic phosphate (Pi) is an essential component of many biologically important molecules such as DNA, RNA, ATP, phospholipids, or apatite. It is required for intracellular phosphorylation signaling events and acts as pH buffer in intra- and extracellular compartments. Intestinal absorption, uptake into cells, and renal reabsorption depend on a set of different phosphate transporters from the SLC20 (PiT transporters) and SLC34 (NaPi transporters) gene families. The physiological relevance of these transporters is evident from rare monogenic disorders in humans affecting SLC20A2 (Fahr's disease, basal ganglia calcification), SLC34A1 (idiopathic infantile hypercalcemia), SLC34A2 (pulmonary alveolar microlithiasis), and SLC34A3 (hereditary hypophosphatemic rickets with hypercalciuria). SLC34 transporters are inhibited by millimolar concentrations of phosphonoformic acid or arsenate while SLC20 are relatively resistant to these compounds. More recently, a series of more specific and potent drugs have been developed to target SLC34A2 to reduce intestinal Pi absorption and to inhibit SLC34A1 and/or SLC34A3 to increase renal Pi excretion in patients with renal disease and incipient hyperphosphatemia. Also, SLC20 inhibitors have been developed with the same intention. Some of these substances are currently undergoing preclinical and clinical testing. Tenapanor, a non-absorbable Na+/H+-exchanger isoform 3 inhibitor, reduces intestinal Pi absorption likely by indirectly acting on the paracellular pathway for Pi and has been tested in several phase III trials for reducing Pi overload in patients with renal insufficiency and dialysis.
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Affiliation(s)
- Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland.
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Fatima N, Ashique S, Upadhyay A, Kumar S, Kumar H, Kumar N, Kumar P. Current Landscape of Therapeutics for the Management of Hypertension - A Review. Curr Drug Deliv 2024; 21:662-682. [PMID: 37357524 DOI: 10.2174/1567201820666230623121433] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 06/27/2023]
Abstract
Hypertension is a critical health problem. It is also the primary reason for coronary heart disease, stroke, and renal vascular disease. The use of herbal drugs in the management of any disease is increasing. They are considered the best immune booster to fight against several types of diseases. To date, the demand for herbal drugs has been increasing because of their excellent properties. This review highlights antihypertensive drugs, polyphenols, and synbiotics for managing hypertension. Evidence is mounting in favour of more aggressive blood pressure control with reduced adverse effects, especially for specific patient populations. This review aimed to present contemporary viewpoints and novel treatment options, including cutting-edge technological applications and emerging interventional and pharmaceutical therapies, as well as key concerns arising from several years of research and epidemiological observations related to the management of hypertension.
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Affiliation(s)
- Neda Fatima
- Department of Pharmacology, Amity University, Lucknow Campus, Lucknow, Uttar Pradesh 226010, India
| | - Sumel Ashique
- Department of Pharmaceutics, Pandaveswar School of Pharmacy, Pandaveswar, West Bengal 713378, India
| | - Aakash Upadhyay
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Shubneesh Kumar
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Himanshu Kumar
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh, 201204, India
| | - Prashant Kumar
- College of Pharmacy, Teerthanker Mahaveer University, Moradabad-244001, UP, India
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Kameda H, Yamaoka K, Yamanishi Y, Tada M, Koike R, Nakajima A, Fusama M, Fujii T. Japan College of Rheumatology guidance for the use of methotrexate in patients with rheumatoid arthritis: Secondary publication. Mod Rheumatol 2023; 34:1-10. [PMID: 37819199 DOI: 10.1093/mr/road098] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/17/2023] [Accepted: 09/23/2023] [Indexed: 10/13/2023]
Abstract
Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6-8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5-15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities.
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Affiliation(s)
- Hideto Kameda
- Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kunihiro Yamaoka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | | | - Masahiro Tada
- Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka, Japan
| | - Ryuji Koike
- Health Science Research and Development Center of Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ayako Nakajima
- Center for Rheumatic Diseases, Mie University Hospital, Mie, Japan
- Department of Rheumatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Mie Fusama
- School of Nursing, Takarazuka University, Osaka, Japan
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan
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Ren F, Jin Q, Jin Q, Qian Y, Ren X, Liu T, Zhan Y. Genetic evidence supporting the causal role of gut microbiota in chronic kidney disease and chronic systemic inflammation in CKD: a bilateral two-sample Mendelian randomization study. Front Immunol 2023; 14:1287698. [PMID: 38022507 PMCID: PMC10652796 DOI: 10.3389/fimmu.2023.1287698] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Background The association of gut microbiota (GM) and chronic kidney disease (CKD), and the relevancy of GM and chronic systemic inflammation in CKD, were revealed on the basis of researches on gut-kidney axis in previous studies. However, their causal relationships are still unclear. Objective To uncover the causal relationships between GM and CKD, as well as all known GM from eligible statistics and chronic systemic inflammation in CKD, we performed two-sample Mendelian randomization (MR) analysis. Materials and methods We acquired the latest and most comprehensive summary statistics of genome-wide association study (GWAS) from the published materials of GWAS involving GM, CKD, estimated glomerular filtration rate (eGFR), c-reactive protein (CRP) and urine albumin creatine ratio (UACR). Subsequently, two-sample MR analysis using the inverse-variance weighted (IVW) method was used to determine the causality of exposure and outcome. Based on it, additional analysis and sensitivity analysis verified the significant results, and the possibility of reverse causality was also assessed by reverse MR analysis during this study. Results At the locus-wide significance threshold, IVW method and additional analysis suggested that the protective factors for CKD included family Lachnospiraceae (P=0.049), genus Eubacterium eligens group (P=0.002), genus Intestinimonas (P=0.009), genus Streptococcu (P=0.003) and order Desulfovibrionales (P=0.001). Simultaneously, results showed that genus LachnospiraceaeUCG010 (P=0.029) was a risk factor for CKD. Higher abundance of genus Desulfovibrio (P=0.048) was correlated with higher eGFR; higher abundance of genus Parasutterella (P=0.018) was correlated with higher UACR; higher abundance of class Negativicutes (P=0.003), genus Eisenbergiella (P=0.021), order Selenomonadales (P=0.003) were correlated with higher CRP levels; higher abundance of class Mollicutes (0.024), family Prevotellaceae (P=0.030), phylum Tenericutes (P=0.024) were correlated with lower levels of CRP. No significant pleiotropy or heterogeneity was found in the results of sensitivity analysis, and no significant causality was found in reverse MR analysis. Conclusion This study highlighted associations within gut-kidney axis, and the causal relationships between GM and CKD, as well as GM and chronic systemic inflammation in CKD were also revealed. Meanwhile, we expanded specific causal gut microbiota through comprehensive searches. With further studies for causal gut microbiota, they may have the potential to be new biomarkers for targeted prevention of CKD and chronic systemic inflammation in CKD.
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Affiliation(s)
- Feihong Ren
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Qiubai Jin
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qi Jin
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yiyun Qian
- Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Xuelei Ren
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tongtong Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yongli Zhan
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Li M, Wang YN, Wang L, Meah WY, Shi DC, Heng KK, Wang L, Khor CC, Bei JX, Cheng CY, Aung T, Liao YH, Chen QK, Gu JR, Kong YZ, Lee J, Chong SA, Subramaniam M, Foo JN, Cai FT, Jiang GR, Xu G, Wan JX, Chen MH, Yin PR, Dong XQ, Feng SZ, Tang XQ, Zhong Z, Tan EK, Chen N, Zhang H, Liu ZH, Tai ES, Liu JJ, Yu XQ. Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy. J Am Soc Nephrol 2023; 34:1900-1913. [PMID: 37787447 PMCID: PMC10631603 DOI: 10.1681/asn.0000000000000222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 08/17/2023] [Indexed: 10/04/2023] Open
Abstract
SIGNIFICANCE STATEMENT Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
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Affiliation(s)
- Ming Li
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yan-Na Wang
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ling Wang
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Wee-Yang Meah
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Dian-Chun Shi
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Khai-Koon Heng
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Li Wang
- Department of Nephrology, Sichuan Provincial People's Hospital, Chengdu, China
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Singapore Eye Research Institute, Singapore, Singapore
| | - Jin-Xin Bei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tin Aung
- Singapore Eye Research Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yun-Hua Liao
- Department of Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Qin-Kai Chen
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jie-Ruo Gu
- Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yao-Zhong Kong
- Department of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Jimmy Lee
- Institute of Mental Health, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | | | - Jia-Nee Foo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Feng-Tao Cai
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Geng-Ru Jiang
- Department of Nephrology, XinHua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gang Xu
- Department of Nephrology, Tongji Hospital, Tongji Medical College of Huazhong University of science & Technology, Wuhan, China
| | - Jian-Xin Wan
- Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Meng-Hua Chen
- Department of Nephrology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Pei-Ran Yin
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Xiu-Qing Dong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Shao-Zhen Feng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Xue-Qing Tang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Zhong Zhong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Eng-King Tan
- Duke-NUS Medical School, Singapore, Singapore
- National Neuroscience Institute, Singapore, Singapore
- Department of Neurology, Singapore General Hospital, Singapore, Singapore
| | - Nan Chen
- Department of Nephrology, RuiJin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Beijing, China
| | - Zhi-Hong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - E. Shyong Tai
- Duke-NUS Medical School, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore
| | - Jian-Jun Liu
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
| | - Xue-Qing Yu
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
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Feng W, Guan Z, Ying WZ, Xing D, Ying KE, Sanders PW. Matrix metalloproteinase-9 regulates afferent arteriolar remodeling and function in hypertension-induced kidney disease. Kidney Int 2023; 104:740-753. [PMID: 37423509 PMCID: PMC10854403 DOI: 10.1016/j.kint.2023.06.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 06/01/2023] [Accepted: 06/22/2023] [Indexed: 07/11/2023]
Abstract
This study tested if matrix metalloproteinase (MMP)-9 promoted microvascular pathology that initiates hypertensive (HT) kidney disease in salt-sensitive (SS) Dahl rats. SS rats lacking Mmp9 (Mmp9-/-) and littermate control SS rats were studied after one week on a normotensive 0.3% sodium chloride (Pre-HT SS and Pre-HT Mmp9-/-) or a hypertension-inducing diet containing 4.0% sodium chloride (HT SS and HT Mmp9-/-). Telemetry-monitored blood pressure of both the HT SS and HT Mmp9-/- rats increased and did not differ. Kidney microvessel transforming growth factor-beta 1 (Tgfb1) mRNA did not differ between Pre-HT SS and Pre-HT Mmp9-/- rats, but with hypertension and expression of Mmp9 and Tgfb1 increased in HT SS rats, along with phospho-Smad2 labeling of nuclei of vascular smooth muscle cells, and with peri-arteriolar fibronectin deposition. Loss of MMP-9 prevented hypertension-induced phenotypic transformation of microvascular smooth muscle cells and the expected increased microvascular expression of pro-inflammatory molecules. Loss of MMP-9 in vascular smooth muscle cells in vitro prevented cyclic strain-induced production of active TGF-β1 and phospho-Smad2/3 stimulation. Afferent arteriolar autoregulation was impaired in HT SS rats but not in HT Mmp9-/- rats or the HT SS rats treated with doxycycline, an MMP inhibitor. HT SS but not HT Mmp9-/- rats showed decreased glomerular Wilms Tumor 1 protein-positive cells (a marker of podocytes) along with increased urinary podocin and nephrin mRNA excretion, all indicative of glomerular damage. Thus, our findings support an active role for MMP-9 in a hypertension-induced kidney microvascular remodeling process that promotes glomerular epithelial cell injury in SS rats.
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Affiliation(s)
- Wenguang Feng
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Zhengrong Guan
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Wei-Zhong Ying
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Dongqi Xing
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kai Er Ying
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Paul W Sanders
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Birmingham Veterans Affairs Health Care System, Birmingham, Alabama, USA.
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Thielemans R, Speeckaert R, Delrue C, De Bruyne S, Oyaert M, Speeckaert MM. Unveiling the Hidden Power of Uromodulin: A Promising Potential Biomarker for Kidney Diseases. Diagnostics (Basel) 2023; 13:3077. [PMID: 37835820 PMCID: PMC10572911 DOI: 10.3390/diagnostics13193077] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Uromodulin, also known as Tamm-Horsfall protein, represents the predominant urinary protein in healthy individuals. Over the years, studies have revealed compelling associations between urinary and serum concentrations of uromodulin and various parameters, encompassing kidney function, graft survival, cardiovascular disease, glucose metabolism, and overall mortality. Consequently, there has been a growing interest in uromodulin as a novel and effective biomarker with potential applications in diverse clinical settings. Reduced urinary uromodulin levels have been linked to an elevated risk of acute kidney injury (AKI) following cardiac surgery. In the context of chronic kidney disease (CKD) of different etiologies, urinary uromodulin levels tend to decrease significantly and are strongly correlated with variations in estimated glomerular filtration rate. The presence of uromodulin in the serum, attributable to basolateral epithelial cell leakage in the thick ascending limb, has been observed. This serum uromodulin level is closely associated with kidney function and histological severity, suggesting its potential as a biomarker capable of reflecting disease severity across a spectrum of kidney disorders. The UMOD gene has emerged as a prominent locus linked to kidney function parameters and CKD risk within the general population. Extensive research in multiple disciplines has underscored the biological significance of the top UMOD gene variants, which have also been associated with hypertension and kidney stones, thus highlighting the diverse and significant impact of uromodulin on kidney-related conditions. UMOD gene mutations are implicated in uromodulin-associated kidney disease, while polymorphisms in the UMOD gene show a significant association with CKD. In conclusion, uromodulin holds great promise as an informative biomarker, providing valuable insights into kidney function and disease progression in various clinical scenarios. The identification of UMOD gene variants further strengthens its relevance as a potential target for better understanding kidney-related pathologies and devising novel therapeutic strategies. Future investigations into the roles of uromodulin and regulatory mechanisms are likely to yield even more profound implications for kidney disease diagnosis, risk assessment, and management.
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Affiliation(s)
- Raïsa Thielemans
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
| | | | - Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
| | - Sander De Bruyne
- Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; (S.D.B.); (M.O.)
| | - Matthijs Oyaert
- Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; (S.D.B.); (M.O.)
| | - Marijn M. Speeckaert
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
- Research Foundation Flanders, 1000 Brussels, Belgium
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Green JR, Mahalingaiah PKS, Gopalakrishnan SM, Liguori MJ, Mittelstadt SW, Blomme EAG, Van Vleet TR. Off-target pharmacological activity at various kinases: Potential functional and pathological side effects. J Pharmacol Toxicol Methods 2023; 123:107468. [PMID: 37553032 DOI: 10.1016/j.vascn.2023.107468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/16/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.
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Affiliation(s)
- Jonathon R Green
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
| | | | - Sujatha M Gopalakrishnan
- Drug Discovery Science and Technology, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Michael J Liguori
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Scott W Mittelstadt
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Eric A G Blomme
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Terry R Van Vleet
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
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Mayanja R, Machipisa T, Soremekun O, Kamiza AB, Kintu C, Kalungi A, Kalyesubula R, Sande OJ, Jjingo D, Fabian J, Robinson-Cohen C, Franceschini N, Nitsch D, Nyirenda M, Zeggini E, Morris AP, Chikowore T, Fatumo S. Genome-wide association analysis of cystatin-C kidney function in continental Africa. EBioMedicine 2023; 95:104775. [PMID: 37639939 PMCID: PMC10474146 DOI: 10.1016/j.ebiom.2023.104775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. METHODS Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). FINDINGS Three independent lead single nucleotide polymorphisms (SNPs) (P-value <5 × 10-8 (based on likelihood ratio test (LRT))) were identified; rs59288815 (ANK3), rs4277141 (OR51B5) and rs911119 (CST3). From fine-mapping, rs59288815 and rs911119 each had a posterior probability of causality of >99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. INTERPRETATION Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. FUNDING Wellcome (220740/Z/20/Z).
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Affiliation(s)
- Richard Mayanja
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University, College of Health Sciences, Kampala, Uganda
| | - Tafadzwa Machipisa
- Department of Medicine, University of Cape Town & Groote Schuur Hospital, Cape Town, South Africa; Clinical Research Laboratory-Genetic and Molecular Epidemiology Laboratory (CRLB-GMEL), Population Health Research Institute (PHRI) & McMaster University, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, Ontario, L8L 2X2, Canada
| | - Opeyemi Soremekun
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
| | - Abram B Kamiza
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Malawi Epidemiology and Intervention Research Unit, Lilongwe, Malawi
| | - Christopher Kintu
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University, College of Health Sciences, Kampala, Uganda
| | - Allan Kalungi
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
| | - Robert Kalyesubula
- Medical Research Council/ Uganda Virus Research Institute (MRC/UVRI) and London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Entebbe, Uganda
| | - Obondo J Sande
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University, College of Health Sciences, Kampala, Uganda
| | - Daudi Jjingo
- African Center of Excellence in Bioinformatics (ACE-B), Makerere University, Kampala, Uganda
| | - June Fabian
- Medical Research Council/Wits University Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Wits Donald Gordon Medical Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Cassianne Robinson-Cohen
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nora Franceschini
- Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | | | - Moffat Nyirenda
- Clinical Research Laboratory-Genetic and Molecular Epidemiology Laboratory (CRLB-GMEL), Population Health Research Institute (PHRI) & McMaster University, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, Ontario, L8L 2X2, Canada; London School of Hygiene and Tropical Medicine London, UK
| | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; TUM School of Medicine, Translational Genomics, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Andrew P Morris
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UK
| | - Tinashe Chikowore
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; MRC/Wits Developmental Pathways for Health Research Unit, Department of Pediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Segun Fatumo
- The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Medical Research Council/ Uganda Virus Research Institute (MRC/UVRI) and London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Entebbe, Uganda; London School of Hygiene and Tropical Medicine London, UK; Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
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48
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Zhang Z, Ji G, Li M. Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD. Front Endocrinol (Lausanne) 2023; 14:1247611. [PMID: 37711901 PMCID: PMC10497960 DOI: 10.3389/fendo.2023.1247611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.
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Affiliation(s)
| | | | - Meng Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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49
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Zhang W, Zhang L, Yang L, Xiao C, Wu X, Yan P, Cui H, Yang C, Zhu J, Wu X, Tang M, Wang Y, Chen L, Liu Y, Zou Y, Zhang L, Yang C, Yao Y, Li J, Liu Z, Zhang B, Jiang X. Migraine, chronic kidney disease and kidney function: observational and genetic analyses. Hum Genet 2023; 142:1185-1200. [PMID: 37306871 PMCID: PMC10449948 DOI: 10.1007/s00439-023-02575-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/23/2023] [Indexed: 06/13/2023]
Abstract
Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (Ncase/Ncontrol = 48,975/540,381), CKD (Ncase/Ncontrol = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10-3), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.
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Affiliation(s)
- Wenqiang Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Li Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Luo Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Urology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Chenghan Xiao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xueyao Wu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Peijing Yan
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Huijie Cui
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Chao Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Jingwei Zhu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Xuan Wu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Mingshuang Tang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Yutong Wang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Lin Chen
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Yunjie Liu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Yanqiu Zou
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Ling Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Iatrical Polymer Material and Artificial Apparatus, School of Polymer Science and Engineering, Sichuan University, Chengdu, China
| | - Chunxia Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Yuqin Yao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jiayuan Li
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
| | - Zhenmi Liu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Ben Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xia Jiang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041 China
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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50
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Josipović J, Šimičević L, Dika Ž, Bulj N, Vrsalović M, Jelaković B. UROMODULIN - A LINK BETWEEN SODIUM EXCRETION AND ALTERATION IN CIRCADIAN BLOOD PRESSURE PATTERN IN PREHYPERTENSIVES. Acta Clin Croat 2023; 62:313-322. [PMID: 38549605 PMCID: PMC10969630 DOI: 10.20471/acc.2023.62.02.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/20/2020] [Indexed: 04/02/2024] Open
Abstract
Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.
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Affiliation(s)
- Josipa Josipović
- Department of Internal Medicine, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
- Catholic University of Croatia, School of Medicine, Zagreb, Croatia
| | - Livija Šimičević
- Department of Laboratory Diagnostics, Zagreb University Hospital Center, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Živka Dika
- Department of Nephrology, Hypertension, Dialysis and Transplantation, Zagreb University Hospital Center, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nikola Bulj
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Cardiology and Angiology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Mislav Vrsalović
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Cardiology and Angiology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Bojan Jelaković
- Department of Nephrology, Hypertension, Dialysis and Transplantation, Zagreb University Hospital Center, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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