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Yao Z, Wang P, Fu Q, Song Q, Xu H, Zhang P. Efficacy and safety of tripterygium glycosides combined with ACEI/ARB on diabetic nephropathy: a meta-analysis. Front Pharmacol 2025; 15:1493590. [PMID: 39898319 PMCID: PMC11782225 DOI: 10.3389/fphar.2024.1493590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
Aims This study aims to evaluate the efficacy and safety of tripterygium glycosides combined with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) in treating Diabetic nephropathy and provide high-level evidence to support its standardized application. Methods Literatures were retrieved from PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, Wanfang and VIP databases, the search time frame was defined as from the time of establishment to April 2023. This study only included randomized controlled trials of tripterygium glycosides combined with ACEI/ARB in the treatment of diabetic nephropathy, and the final included studies were identified according to the inclusion and exclusion criteria, and meta-analysis of data was performed using RevMan 5.3 software. Results A total of 44 RCTs with 3537 DN patients were included in the study. Compared with the control group, tripterygium glycosides combined with ACEI/ARB significantly reducing 24 h-UTP (24 h urine total protein) [SMD = -1.46, 95% CI (-1.70, -1.23), P < 0.00001], increasing effective rate [RR = 1.23, 95% CI (1.17,1.29), P < 0.00001], elevating serum albumin [SMD = 0.85, 95% CI (0.69, 1.02), P < 0.00001], improving serum creatinine [SMD = -0.35, 95% CI (-0.59, -0.11), P = 0.004], with no difference in BUN (blood urea nitrogen) [SMD = -0.17, 95% CI (-0.48,0.13), P = 0.27], the adverse reactions rate was higher than those of the control group [RR = 1.96, 95%CI (1.43, 2.68), P < 0.0001]. Conclusion This study showed that the combination of tripterygium glycosides and ACEI/ARB was more effective than ACEI/ARB alone. However, the side effects of the combined treatment group were higher than those of the control group, especially liver function damage, which also suggested that its safety in the treatment of diabetic nephropathy was worth considering. Therefore, although tripterygium glycosides provided a choice for the clinical treatment of diabetic nephropathy, its side effects limited its clinical application. In future studies, we need to further optimize tripterygium glycosides and reduce its side effects to ensure the safety of clinical application.
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Affiliation(s)
- Zhuan’E. Yao
- Department of Nephrology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
- Department of Nephrology, Shaanxi Provincial Second People’s Hospital, Xi’an, Shaanxi, China
| | - Pengbo Wang
- Department of Nephrology, Shaanxi Provincial Second People’s Hospital, Xi’an, Shaanxi, China
| | - Qinjuan Fu
- Department of Nephrology, Shaanxi Provincial Second People’s Hospital, Xi’an, Shaanxi, China
| | - Qiong Song
- Department of Nephrology, Shaanxi Provincial Second People’s Hospital, Xi’an, Shaanxi, China
| | - Haojian Xu
- Department of Nephrology, Shaanxi Provincial Second People’s Hospital, Xi’an, Shaanxi, China
| | - Peng Zhang
- Department of Nephrology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
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Zhang L, Tian M, Zhang M, Li C, Wang X, Long Y, Wang Y, Hu J, Chen C, Chen X, Liang W, Ding G, Gan H, Liu L, Wang H. Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405325. [PMID: 39083268 PMCID: PMC11423168 DOI: 10.1002/advs.202405325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/17/2024] [Indexed: 09/26/2024]
Abstract
Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.
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Affiliation(s)
- Lu Zhang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Maoqing Tian
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Meng Zhang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Chen Li
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Xiaofei Wang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Yuyu Long
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Yujuan Wang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Jijia Hu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Cheng Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Xinghua Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Wei Liang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Guohua Ding
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
| | - Hua Gan
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lunzhi Liu
- Hubei Provincial Clinical Medical Research Center for Nephropathy, Minda Hospital of Hubei Minzu University, Enshi, Hubei, 445000, China
| | - Huiming Wang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
- Hubei Provincial Clinical Research Center for Kidney Disease, Wuhan, Hubei, 430060, China
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Chen X, Zou B, Yang Z. CircACTR2 attenuated the effects of tetramethylpyrazine on human kidney cell injury. J Bioenerg Biomembr 2024; 56:273-284. [PMID: 38427129 DOI: 10.1007/s10863-024-10001-6] [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: 08/03/2023] [Accepted: 01/05/2024] [Indexed: 03/02/2024]
Abstract
Tetramethylpyrazine (TMP) is one of the active ingredients of Chuan Xiong that has been reported to have effects on numerous diseases, including diabetic nephropathy (DN). Whereas, related molecular mechanisms are not fully elucidated. We aimed to explore circACTR2's role in TMP-mediated protective effects on DN. In vitro DN condition was established in human kidney cells (HK-2) by treating high glucose (HG). CCK-8 assay and flow cytometry assay were used to observe cell viability and survival. Oxidative stress was determined by the associated markers using kits. The release of inflammatory factors was detected using ELISA kits. Quantitative real-time PCR (qPCR) and western blot were utilized for expression analysis of cricACTR2, miR-140-5p, and GLI pathogenesis-related 2 (GLIPR2). The binding between miR-140-5p and circACTR2 or GLIPR2 was confirmed by dual-luciferase, RIP, and pull-down studies. HG largely induced HK-2 cell apoptosis, oxidative stress, and inflammation, which were alleviated by TMP. CircACTR2's expression was enhanced in HG-treated HK-2 cells but attenuated in HG + TMP-treated HK-2 cells. CircACTR2 overexpression attenuated the functional effects of TMP and thus restored HG-induced cell apoptosis, oxidative stress, and inflammation. CircACTR2 bound to miR-140-5p to enhance the expression of GLIPR2. MiR-140-5p restoration or GLIPR2 inhibition reversed the role of circACTR2 overexpression. CircACTR2 attenuated the protective effects of TMP on HG-induced HK-2 cell damages by regulating the miR-140-5p/GLIPR2 network, indicating that circACTR2 was involved in the functional network of TMP in DN.
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Affiliation(s)
- Xiuzhi Chen
- Department of endocrinology, Taihe Hospital of traditional Chinese Medicine, No. 59 Tuanjie West Road, Taihe County, Fuyang, 236600, Anhui, China.
| | - Bin Zou
- Department of endocrinology, Taihe Hospital of traditional Chinese Medicine, No. 59 Tuanjie West Road, Taihe County, Fuyang, 236600, Anhui, China
| | - Zhen Yang
- Department of endocrinology, Taihe Hospital of traditional Chinese Medicine, No. 59 Tuanjie West Road, Taihe County, Fuyang, 236600, Anhui, China
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Clotet-Freixas S, Zaslaver O, Kotlyar M, Pastrello C, Quaile AT, McEvoy CM, Saha AD, Farkona S, Boshart A, Zorcic K, Neupane S, Manion K, Allen M, Chan M, Chen X, Arnold AP, Sekula P, Steinbrenner I, Köttgen A, Dart AB, Wicklow B, McGavock JM, Blydt-Hansen TD, Barrios C, Riera M, Soler MJ, Isenbrandt A, Lamontagne-Proulx J, Pradeloux S, Coulombe K, Soulet D, Rajasekar S, Zhang B, John R, Mehrotra A, Gehring A, Puhka M, Jurisica I, Woo M, Scholey JW, Röst H, Konvalinka A. Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease. Sci Transl Med 2024; 16:eabm2090. [PMID: 38446901 DOI: 10.1126/scitranslmed.abm2090] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/24/2024] [Indexed: 03/08/2024]
Abstract
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.
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Affiliation(s)
- Sergi Clotet-Freixas
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Olga Zaslaver
- Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Max Kotlyar
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Andrew T Quaile
- Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Caitriona M McEvoy
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
- Division of Nephrology, Tallaght University Hospital, Dublin D24, Ireland
- Trinity Kidney Centre, Trinity College Dublin, Dublin D8, Ireland
| | - Aninda D Saha
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Alex Boshart
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Katarina Zorcic
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Slaghaniya Neupane
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Kieran Manion
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Maya Allen
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Michael Chan
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Xuqi Chen
- Department of Integrative Biology & Physiology, University of California, Los Angeles, CA 90095, USA
| | - Arthur P Arnold
- Department of Integrative Biology & Physiology, University of California, Los Angeles, CA 90095, USA
| | - Peggy Sekula
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg 79085, Germany
| | - Inga Steinbrenner
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg 79085, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg 79085, Germany
| | - Allison B Dart
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba Research Team, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Brandy Wicklow
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba Research Team, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Jon M McGavock
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba Research Team, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 0B3, Canada
| | - Clara Barrios
- Kidney Research Group, Hospital del Mar Medical Research Institute, IMIM, Barcelona 08003, Spain
| | - Marta Riera
- Kidney Research Group, Hospital del Mar Medical Research Institute, IMIM, Barcelona 08003, Spain
| | - María José Soler
- Hospital Universitari Vall d'Hebron, Division of Nephrology Autonomous University of Barcelona, Barcelona 08035, Spain
| | - Amandine Isenbrandt
- Neurosciences Axis, CHU de Quebec Research Center - Université Laval, Québec, QC G1V 4G2, Canada
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Jérôme Lamontagne-Proulx
- Neurosciences Axis, CHU de Quebec Research Center - Université Laval, Québec, QC G1V 4G2, Canada
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Solène Pradeloux
- Neurosciences Axis, CHU de Quebec Research Center - Université Laval, Québec, QC G1V 4G2, Canada
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Katherine Coulombe
- Neurosciences Axis, CHU de Quebec Research Center - Université Laval, Québec, QC G1V 4G2, Canada
| | - Denis Soulet
- Neurosciences Axis, CHU de Quebec Research Center - Université Laval, Québec, QC G1V 4G2, Canada
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Shravanthi Rajasekar
- Department of Chemical Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Boyang Zhang
- Department of Chemical Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada
- School of Biomedical Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Rohan John
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Aman Mehrotra
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Maija Puhka
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki 00014, Finland
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
- Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1X3, Canada
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava 845 10, Slovakia
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medicine, Division of Endocrinology, University Health Network, University of Toronto, Toronto, ON M5S 3H2, Canada
| | - James W Scholey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON M5S 3H2, Canada
| | - Hannes Röst
- Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON M5S 3H2, Canada
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Satyadev N, Rivera MI, Nikolov NK, Fakoya AOJ. Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications. Front Physiol 2023; 14:1241096. [PMID: 37745252 PMCID: PMC10515224 DOI: 10.3389/fphys.2023.1241096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.
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Affiliation(s)
- Nihal Satyadev
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Milagros I. Rivera
- University of Medicine and Health Sciences, Basseterre, St. Kitts and Nevis
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Advances in the Pharmacological Management of Diabetic Nephropathy: A 2022 International Update. Biomedicines 2023; 11:biomedicines11020291. [PMID: 36830828 PMCID: PMC9953496 DOI: 10.3390/biomedicines11020291] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/24/2022] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. Its pathogenesis encompasses functional alterations involving elevated intraglomerular and systemic pressure, increased activity of the renin-angiotensin system (RAS) and oxidative stress, and the eventual development of renal fibrosis. The management of DN involves the optimization of blood pressure (BP) and blood glucose targets. However, treatment of these risk factors slows down but does not stop the progression of DN. Innovative pharmacologic therapies for dyslipidemia and type 2 diabetes mellitus (T2DM) could play a key role in bridging this gap and attenuating the residual risk of DN beyond traditional risk factor management. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is), and inhibitors of mineralocorticoid receptor-mediated sodium reabsorption are recently introduced drug classes that have been shown to have positive effects on kidney function in individuals with T2DM. The aim of this review is to provide an update on the therapeutic options available in order to prevent or slow the onset and progression of DN in diabetic patients.
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Zhu X, Xu X, Du C, Su Y, Yin L, Tan X, Liu H, Wang Y, Xu L, Xu X. An examination of the protective effects and molecular mechanisms of curcumin, a polyphenol curcuminoid in diabetic nephropathy. Biomed Pharmacother 2022; 153:113438. [DOI: 10.1016/j.biopha.2022.113438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 11/02/2022] Open
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Shi H, Xiang T, Feng J, Yang X, Li Y, Fang Y, Xu L, Qi Q, Shen J, Tang L, Shen Q, Wang X, Xu H, Rao J. N6-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy. Front Med (Lausanne) 2022; 9:924579. [PMID: 35795641 PMCID: PMC9251069 DOI: 10.3389/fmed.2022.924579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Background Congenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N6-methyladenosine (m6A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m6A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m6A methylation in CAKUT. Methods Using m6A-mRNA epitranscriptomic microarray, we investigated the m6A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group). Results A total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m6A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m6A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m6A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison. Conclusion The current results highlight the pathogenesis of m6A methylation in obstructive and reflux uropathy.
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Affiliation(s)
- Hua Shi
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Tianchao Xiang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Jiayan Feng
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - Xue Yang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Yaqi Li
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Ye Fang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Linan Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Qi Qi
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Jian Shen
- Department of Urology, Children's Hospital of Fudan University, Shanghai, China
| | - Liangfeng Tang
- Department of Urology, Children's Hospital of Fudan University, Shanghai, China
| | - Qian Shen
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Xiang Wang
- Department of Urology, Children's Hospital of Fudan University, Shanghai, China
- *Correspondence: Xiang Wang
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
- Hong Xu
| | - Jia Rao
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and School of Basic Medical Science, Fudan University, Shanghai, China
- Jia Rao
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9
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Boi R, Ebefors K, Henricsson M, Borén J, Nyström J. Modified lipid metabolism and cytosolic phospholipase A2 activation in mesangial cells under pro-inflammatory conditions. Sci Rep 2022; 12:7322. [PMID: 35513427 PMCID: PMC9072365 DOI: 10.1038/s41598-022-10907-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/08/2022] [Indexed: 02/07/2023] Open
Abstract
Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of the mesangium are yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. Stimulation of human mesangial cells with high glucose primed the inflammasome-driven interleukin 1 beta (IL-1β) secretion, which in turn stimulated platelet-derived growth factor (PDGF-BB) release. Finally, PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimulation triggered the formation of phosphorylated sphingoid bases, as shown by lipidomics, and activated cytosolic phospholipase cPLA2, sphingosine kinase 1, cyclooxygenase 2, and autotaxin. This led to the release of arachidonic acid and lysophosphatidylcholine, activating the secretion of vasodilatory prostaglandins and proliferative lysophosphatidic acids. Blocking cPLA2 release of arachidonic acid reduced mesangial cells proliferation and prostaglandin secretion. Validation was performed in silico using the Nephroseq database and a glomerular transcriptomic database. In conclusion, hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in human mesangial cells. The upregulation of cPLA2 was critical in this setting. Its inhibition reduced mesangial secretion of prostaglandins and proliferation, making it a potential therapeutical target.
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Affiliation(s)
- Roberto Boi
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden
| | - Kerstin Ebefors
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden
| | - Marcus Henricsson
- Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jan Borén
- Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jenny Nyström
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden.
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10
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Zhou Y, Yu Z, Liu L, Wei L, Zhao L, Huang L, Wang L, Sun S. Construction and evaluation of an integrated predictive model for chronic kidney disease based on the random forest and artificial neural network approaches. Biochem Biophys Res Commun 2022; 603:21-28. [PMID: 35276459 DOI: 10.1016/j.bbrc.2022.02.099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/23/2022] [Indexed: 12/18/2022]
Abstract
Chronic kidney disease (CKD) is recognized as a serious global health problem due to its high prevalence and all-cause mortality. The aim of this research was to identify critical biomarkers and construct an integrated model for the early prediction of CKD. By using existing RNA-seq data and clinical information from CKD patients from the Gene Expression Omnibus (GEO) database, we applied a computational technique that combined the random forest (RF) and artificial neural network (ANN) approaches to identify gene biomarkers and construct an early diagnostic model. We generated ROC curves to compare the model with other markers and evaluated the associations of selected genes with various clinical properties of CKD. Moreover, we highlighted two biomarkers involved in energy metabolism pathways: pyruvate dehydrogenase kinase 4 (PDK4) and zinc finger protein 36 (ZFP36). The downregulation of the identified key genes was subsequently confirmed in both unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) mouse models, accompanied by decreased energy metabolism. In vitro experiments and single-cell sequencing analysis proved that these key genes were related to the energy metabolism of proximal tubule cells and were involved in the development of CKD. Overall, we constructed a composite prediction model and discovered key genes that might be used as biomarkers and therapeutic targets for CKD.
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Affiliation(s)
- Ying Zhou
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Geriatrics, General Hospital of Central Theater Command, Wuhan, Hubei, 430070, China
| | - Zhixiang Yu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Limin Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Lei Wei
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Lijuan Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Liuyifei Huang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Liya Wang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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11
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Deleersnijder D, Van Craenenbroeck AH, Sprangers B. Deconvolution of Focal Segmental Glomerulosclerosis Pathophysiology Using Transcriptomics Techniques. GLOMERULAR DISEASES 2021; 1:265-276. [PMID: 36751384 PMCID: PMC9677714 DOI: 10.1159/000518404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/08/2021] [Indexed: 11/19/2022]
Abstract
Background Focal segmental glomerulosclerosis is a histopathological pattern of renal injury and comprises a heterogeneous group of clinical conditions with different pathophysiology, clinical course, prognosis, and treatment. Nevertheless, subtype differentiation in clinical practice often remains challenging, and we currently lack reliable diagnostic, prognostic, and therapeutic biomarkers. The advent of new transcriptomics techniques in kidney research poses great potential in the identification of gene expression biomarkers that can be applied in clinical practice. Summary Transcriptomics techniques have been completely revolutionized in the last 2 decades, with the evolution from low-throughput reverse-transcription polymerase chain reaction and in situ hybridization techniques to microarrays and next-generation sequencing techniques, including RNA-sequencing and single-cell transcriptomics. The integration of human gene expression profiles with functional in vitro and in vivo experiments provides a deeper mechanistic insight into the candidate genes, which enable the development of novel-targeted therapies. The correlation of gene expression profiles with clinical outcomes of large patient cohorts allows for the development of clinically applicable biomarkers that can aid in diagnosis and predict prognosis and therapy response. Finally, the integration of transcriptomics with other "omics" modalities creates a holistic view on disease pathophysiology. Key Messages New transcriptomics techniques allow high-throughput gene expression profiling of patients with focal segmental glomerulosclerosis (FSGS). The integration with clinical outcomes and fundamental mechanistic studies enables the discovery of new clinically useful biomarkers that will finally improve the clinical outcome of patients with FSGS.
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Affiliation(s)
- Dries Deleersnijder
- Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium,Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Amaryllis H. Van Craenenbroeck
- Division of Nephrology, University Hospitals Leuven, Leuven, Belgium,Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium,Division of Nephrology, University Hospitals Leuven, Leuven, Belgium,*Ben Sprangers,
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12
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Matías-García PR, Wilson R, Guo Q, Zaghlool SB, Eales JM, Xu X, Charchar FJ, Dormer J, Maalmi H, Schlosser P, Elhadad MA, Nano J, Sharma S, Peters A, Fornoni A, Mook-Kanamori DO, Winkelmann J, Danesh J, Di Angelantonio E, Ouwehand WH, Watkins NA, Roberts DJ, Petrera A, Graumann J, Koenig W, Hveem K, Jonasson C, Köttgen A, Butterworth A, Prunotto M, Hauck SM, Herder C, Suhre K, Gieger C, Tomaszewski M, Teumer A, Waldenberger M. Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study. J Am Soc Nephrol 2021; 32:1747-1763. [PMID: 34135082 PMCID: PMC8425654 DOI: 10.1681/asn.2020071070] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/24/2021] [Accepted: 03/22/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
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Affiliation(s)
- Pamela R. Matías-García
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- TUM School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Cardiovascular Research, Munich, Germany
| | - Rory Wilson
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
| | - Qi Guo
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Shaza B. Zaghlool
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - James M. Eales
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Xiaoguang Xu
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Fadi J. Charchar
- School of Health and Life Sciences, Federation University Australia, Ballarat, Australia
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
- Department of Physiology, University of Melbourne, Melbourne, Australia
| | - John Dormer
- Department of Cellular Pathology, University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom
| | - Haifa Maalmi
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | - Pascal Schlosser
- Department of Data-Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany
| | - Mohamed A. Elhadad
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Cardiovascular Research, Munich, Germany
| | - Jana Nano
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | - Sapna Sharma
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
| | - Annette Peters
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Cardiovascular Research, Munich, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | - Alessia Fornoni
- Department of Medicine, Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida
| | - Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Juliane Winkelmann
- Institute of Neurogenomics, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Neurogenetics and Institute of Human Genetics, Technical University of Munich, Munich, Germany
| | - John Danesh
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
- National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
- Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
| | - Emanuele Di Angelantonio
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
- National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
| | - Willem H. Ouwehand
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, United Kingdom
- Wellcome Sanger Institute, Hinxton, United Kingdom
| | - Nicholas A. Watkins
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, United Kingdom
| | - David J. Roberts
- National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
- National Health Service Blood and Transplant Oxford Centre, Oxford, United Kingdom
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Agnese Petrera
- Research Unit Protein Science and Metabolomics and Proteomics Core Facility, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Johannes Graumann
- Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute of Heart and Lung Research, Bad Nauheim, Germany
| | - Wolfgang Koenig
- German Center for Cardiovascular Research, Munich, Germany
- Klinik für Herz-Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University of Munich, Munich, Germany
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Kristian Hveem
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- Nord-Trøndelag Health Study HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway
| | - Christian Jonasson
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- Nord-Trøndelag Health Study HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway
| | - Anna Köttgen
- Department of Data-Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Adam Butterworth
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Marco Prunotto
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
| | - Stefanie M. Hauck
- Research Unit Protein Science and Metabolomics and Proteomics Core Facility, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Christian Gieger
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Cardiovascular Research, Munich, Germany
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
- Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Alexander Teumer
- Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Cardiovascular Research, partner site Greifswald, Greifswald, Germany
| | - Melanie Waldenberger
- Research Unit Molecular Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Cardiovascular Research, Munich, Germany
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13
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Abstract
Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease for over 20 years. Yet, over these two decades, the clinical approach to this condition has not much improved beyond the administration of glucose-lowering agents, renin-angiotensin-aldosterone system blockers for blood pressure control, and lipid-lowering agents. The proportion of diabetic patients who develop DKD and progress to end-stage renal disease has remained nearly the same. This unmet need for DKD treatment is caused by the complex pathophysiology of DKD, and the difficulty of translating treatment from bench to bed, which further adds to the growing argument that DKD is not a homogeneous disease. To better capture the full spectrum of DKD in our design of treatment regimens, we need improved diagnostic tools that can better distinguish the subgroups within the condition. For instance, DKD is typically placed in the broad category of a non-inflammatory kidney disease. However, genome-wide transcriptome analysis studies consistently indicate the inflammatory signaling pathway activation in DKD. This review will utilize human data in discussing the potential for redefining the role of inflammation in DKD. We also comment on the therapeutic potential of targeted anti-inflammatory therapy for DKD.
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Affiliation(s)
- Su Woong Jung
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
- Correspondence to Ju-Young Moon, M.D. Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea Tel: +82-2-440-7064 Fax: +82-2-440-8150 E-mail:
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14
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Shalaby K, Bahriz R, Mahsoub N, El-Arman MM, El-Said G. Matrix metalloproteinase-9 gene polymorphism (-1562 C/T) and its correlation with diabetic nephropathy. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2021. [DOI: 10.1186/s43162-021-00035-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023] Open
Abstract
Abstract
Background
Matrix metalloproteinase 9 (MMP-9) is an important inflammatory marker in diabetic nephropathy. Many studies assessed the association between MMP-9 gene polymorphism and different microvascular complications of type 2 diabetes mellitus, though the results were inconclusive and need further exploration. Our study aimed to assess the association between MMP-9 -1562C/T gene polymorphism and diabetic nephropathy in patients with type 2 diabetes mellitus.
Results
Taking CC genotype of rs3918242 (MMP-9-1562C/T SNP) as the reference genotype and C as the reference allele, TT genotype, T allele showed significantly lower frequency in diabetic nephropathy group than without nephropathy (2.9% versus 20%, 20% versus 35.7% respectively), with the possible significant protective effect against diabetic nephropathy development (OR = 0.269, 0.450 respectively); it was considered as an independent predictor for diabetic nephropathy occurrence.
Conclusions
This study suggested that T allele of MMP-9 -1562C/T single nucleotide polymorphism had a protective role against diabetic nephropathy development and also had a role for early prediction of patients susceptible to this complication, so it helps in prevention and management of those patients.
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15
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Zhang L, Wang Z, Liu R, Li Z, Lin J, Wojciechowicz ML, Huang J, Lee K, Ma'ayan A, He JC. Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease. Diabetes 2021; 70:589-602. [PMID: 33067313 PMCID: PMC7881868 DOI: 10.2337/db20-0580] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-α/NF-κB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-κB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
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Affiliation(s)
- Lu Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Zichen Wang
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Ruijie Liu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Zhengzhe Li
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jennifer Lin
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Megan L Wojciechowicz
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jiyi Huang
- Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Avi Ma'ayan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Renal Section, James J. Peters Veterans Affair Medical Center, Bronx, NY
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16
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Eddy S, Mariani LH, Kretzler M. Integrated multi-omics approaches to improve classification of chronic kidney disease. Nat Rev Nephrol 2020; 16:657-668. [PMID: 32424281 DOI: 10.1038/s41581-020-0286-5] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2020] [Indexed: 12/11/2022]
Abstract
Chronic kidney diseases (CKDs) are currently classified according to their clinical features, associated comorbidities and pattern of injury on biopsy. Even within a given classification, considerable variation exists in disease presentation, progression and response to therapy, highlighting heterogeneity in the underlying biological mechanisms. As a result, patients and clinicians experience uncertainty when considering optimal treatment approaches and risk projection. Technological advances now enable large-scale datasets, including DNA and RNA sequence data, proteomics and metabolomics data, to be captured from individuals and groups of patients along the genotype-phenotype continuum of CKD. The ability to combine these high-dimensional datasets, in which the number of variables exceeds the number of clinical outcome observations, using computational approaches such as machine learning, provides an opportunity to re-classify patients into molecularly defined subgroups that better reflect underlying disease mechanisms. Patients with CKD are uniquely poised to benefit from these integrative, multi-omics approaches since the kidney biopsy, blood and urine samples used to generate these different types of molecular data are frequently obtained during routine clinical care. The ultimate goal of developing an integrated molecular classification is to improve diagnostic classification, risk stratification and assignment of molecular, disease-specific therapies to improve the care of patients with CKD.
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Affiliation(s)
- Sean Eddy
- Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Laura H Mariani
- Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Matthias Kretzler
- Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA.
- Department of Computational Medicine and Bioinformatics, Michigan Medicine, Ann Arbor, MI, USA.
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17
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Rinschen MM, Saez-Rodriguez J. The tissue proteome in the multi-omic landscape of kidney disease. Nat Rev Nephrol 2020; 17:205-219. [PMID: 33028957 DOI: 10.1038/s41581-020-00348-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2020] [Indexed: 02/07/2023]
Abstract
Kidney research is entering an era of 'big data' and molecular omics data can provide comprehensive insights into the molecular footprints of cells. In contrast to transcriptomics, proteomics and metabolomics generate data that relate more directly to the pathological symptoms and clinical parameters observed in patients. Owing to its complexity, the proteome still holds many secrets, but has great potential for the identification of drug targets. Proteomics can provide information about protein synthesis, modification and degradation, as well as insight into the physical interactions between proteins, and between proteins and other biomolecules. Thus far, proteomics in nephrology has largely focused on the discovery and validation of biomarkers, but the systematic analysis of the nephroproteome can offer substantial additional insights, including the discovery of mechanisms that trigger and propagate kidney disease. Moreover, proteome acquisition might provide a diagnostic tool that complements the assessment of a kidney biopsy sample by a pathologist. Such applications are becoming increasingly feasible with the development of high-throughput and high-coverage technologies, such as versatile mass spectrometry-based techniques and protein arrays, and encourage further proteomics research in nephrology.
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Affiliation(s)
- Markus M Rinschen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark. .,III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. .,Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. .,Department of Chemistry, Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research, La Jolla, CA, USA.
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany.,Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany.,Molecular Medicine Partnership Unit, European Molecular Biology Laboratory and Heidelberg University, Heidelberg, Germany
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18
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Ge X, Zhang T, Yu X, Muwonge AN, Anandakrishnan N, Wong NJ, Haydak JC, Reid JM, Fu J, Wong JS, Bhattacharya S, Cuttitta CM, Zhong F, Gordon RE, Salem F, Janssen W, Hone JC, Zhang A, Li H, He JC, Gusella GL, Campbell KN, Azeloglu EU. LIM-Nebulette Reinforces Podocyte Structural Integrity by Linking Actin and Vimentin Filaments. J Am Soc Nephrol 2020; 31:2372-2391. [PMID: 32737144 DOI: 10.1681/asn.2019121261] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 06/06/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Maintenance of the intricate interdigitating morphology of podocytes is crucial for glomerular filtration. One of the key aspects of specialized podocyte morphology is the segregation and organization of distinct cytoskeletal filaments into different subcellular components, for which the exact mechanisms remain poorly understood. METHODS Cells from rats, mice, and humans were used to describe the cytoskeletal configuration underlying podocyte structure. Screening the time-dependent proteomic changes in the rat puromycin aminonucleoside-induced nephropathy model correlated the actin-binding protein LIM-nebulette strongly with glomerular function. Single-cell RNA sequencing and immunogold labeling were used to determine Nebl expression specificity in podocytes. Automated high-content imaging, super-resolution microscopy, atomic force microscopy (AFM), live-cell imaging of calcium, and measurement of motility and adhesion dynamics characterized the physiologic role of LIM-nebulette in podocytes. RESULTS Nebl knockout mice have increased susceptibility to adriamycin-induced nephropathy and display morphologic, cytoskeletal, and focal adhesion abnormalities with altered calcium dynamics, motility, and Rho GTPase activity. LIM-nebulette expression is decreased in diabetic nephropathy and FSGS patients at both the transcript and protein level. In mice, rats, and humans, LIM-nebulette expression is localized to primary, secondary, and tertiary processes of podocytes, where it colocalizes with focal adhesions as well as with vimentin fibers. LIM-nebulette shRNA knockdown in immortalized human podocytes leads to dysregulation of vimentin filament organization and reduced cellular elasticity as measured by AFM indentation. CONCLUSIONS LIM-nebulette is a multifunctional cytoskeletal protein that is critical in the maintenance of podocyte structural integrity through active reorganization of focal adhesions, the actin cytoskeleton, and intermediate filaments.
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Affiliation(s)
- Xuhua Ge
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tao Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Xiaoxia Yu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alecia N Muwonge
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nanditha Anandakrishnan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nicholas J Wong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jonathan C Haydak
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jordan M Reid
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jia Fu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jenny S Wong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Smiti Bhattacharya
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Mechanical Engineering, Columbia University, New York, New York
| | - Christina M Cuttitta
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Fang Zhong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ronald E Gordon
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Fadi Salem
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - William Janssen
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
| | - James C Hone
- Department of Mechanical Engineering, Columbia University, New York, New York
| | - Aihua Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hong Li
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University-New Jersey Medical School, Newark, New Jersey
| | - John C He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - G Luca Gusella
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kirk N Campbell
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Evren U Azeloglu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York .,Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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19
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Hu H, Li W, Liu M, Xiong J, Li Y, Wei Y, Huang C, Tang Y. C1q/Tumor Necrosis Factor-Related Protein-9 Attenuates Diabetic Nephropathy and Kidney Fibrosis in db/db Mice. DNA Cell Biol 2020; 39:938-948. [PMID: 32283037 DOI: 10.1089/dna.2019.5302] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy (DN) is characterized by excessive accumulation of extracellular matrix leading to early thickening of glomerular and tubular basement membrane. C1q/tumor necrosis factor (TNF)-related protein-9 (CTRP9) was recently identified as an adiponectin paralog of superior prominence. CTRP9 is an anti-inflammatory, antioxidant, vasodilation and atheroprotective adipose cytokine that share a similar metabolic regulatory function as adiponectin. Additionally, CTRP9 inhibits apoptosis of endothelial cells, decreases blood glucose level, and increases insulin sensitivity. However, the renoprotective effects of CTRP9 and the underlying molecular mechanisms in DN have not been explored. This study examined the effects of CTRP9 on DN in diabetic db/db mice through adenovirus-mediated overexpression. From the results, CTRP9 ameliorated renal dysfunction and injury at the structural and functional level in diabetic db/db mice. Additionally, CTRP9 inhibited glomerular and tubular glycogen accumulation, fibrosis, relieved hyperglycemia-mediated oxidative stress, and apoptosis. This is the first study to report on therapeutic effects of CTRP9 on DN, presenting a potentially effective clinical treatment method for DN patients.
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Affiliation(s)
- Hongyao Hu
- Department of Interventional Radiology, Department of Radiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
| | - Wei Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Mingxin Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Jiarui Xiong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Yanjun Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Yanzhao Wei
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Congxin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
| | - Yanhong Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan, P.R. China
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20
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Eid SA, El Massry M, Hichor M, Haddad M, Grenier J, Dia B, Barakat R, Boutary S, Chanal J, Aractingi S, Wiesel P, Szyndralewiez C, Azar ST, Boitard C, Zaatari G, Eid AA, Massaad C. Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice. Diabetes 2020; 69:448-464. [PMID: 31882567 DOI: 10.2337/db19-0517] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 12/15/2019] [Indexed: 11/13/2022]
Abstract
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.
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Affiliation(s)
- Stéphanie A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mohamed El Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mehdi Hichor
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mary Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Julien Grenier
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Batoul Dia
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Rasha Barakat
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Suzan Boutary
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Johan Chanal
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Selim Aractingi
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | | | | | - Sami T Azar
- Department of Internal Medicine, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- AUB Diabetes, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Christian Boitard
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Ghazi Zaatari
- Department of Pathology, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- AUB Diabetes, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Charbel Massaad
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
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21
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Rowland J, Akbarov A, Eales J, Xu X, Dormer JP, Guo H, Denniff M, Jiang X, Ranjzad P, Nazgiewicz A, Prestes PR, Antczak A, Szulinska M, Wise IA, Zukowska-Szczechowska E, Bogdanski P, Woolf AS, Samani NJ, Charchar FJ, Tomaszewski M. Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics. Kidney Int 2020; 95:624-635. [PMID: 30784661 PMCID: PMC6390171 DOI: 10.1016/j.kint.2018.10.029] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 10/15/2018] [Accepted: 10/18/2018] [Indexed: 12/19/2022]
Abstract
Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
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Affiliation(s)
- Joshua Rowland
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Artur Akbarov
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - James Eales
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Xiaoguang Xu
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - John P Dormer
- Department of Cellular Pathology, University Hospitals of Leicester, Leicester, UK
| | - Hui Guo
- Division of Population Health, Health Services Research and Primary Care, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Matthew Denniff
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Xiao Jiang
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Parisa Ranjzad
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Alicja Nazgiewicz
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | | | - Andrzej Antczak
- Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Monika Szulinska
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Ingrid A Wise
- Faculty of Health and Life Sciences, Federation University Australia, Ballarat, Victoria, Australia
| | - Ewa Zukowska-Szczechowska
- Department of Health Care, Silesian Medical College, Katowice, Poland; Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland
| | - Pawel Bogdanski
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Adrian S Woolf
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK; Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester University National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; Leicester National Institute for Health Research Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Fadi J Charchar
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; Faculty of Health and Life Sciences, Federation University Australia, Ballarat, Victoria, Australia; Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK; Division of Medicine and Manchester Heart Centre, Manchester University National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
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22
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Donate-Correa J, Luis-Rodríguez D, Martín-Núñez E, Tagua VG, Hernández-Carballo C, Ferri C, Rodríguez-Rodríguez AE, Mora-Fernández C, Navarro-González JF. Inflammatory Targets in Diabetic Nephropathy. J Clin Med 2020; 9:jcm9020458. [PMID: 32046074 PMCID: PMC7074396 DOI: 10.3390/jcm9020458] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/31/2022] Open
Abstract
One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
| | - Desirée Luis-Rodríguez
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | - Víctor G. Tagua
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
| | | | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | | | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38010 San Cristóbal de La Laguna, Spain
- Correspondence: ; Tel.: +34-922-602-389
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23
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Tajti F, Kuppe C, Antoranz A, Ibrahim MM, Kim H, Ceccarelli F, Holland CH, Olauson H, Floege J, Alexopoulos LG, Kramann R, Saez-Rodriguez J. A Functional Landscape of CKD Entities From Public Transcriptomic Data. Kidney Int Rep 2019; 5:211-224. [PMID: 32043035 PMCID: PMC7000845 DOI: 10.1016/j.ekir.2019.11.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 10/09/2019] [Accepted: 11/04/2019] [Indexed: 12/18/2022] Open
Abstract
Introduction To develop effective therapies and identify novel early biomarkers for chronic kidney disease, an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in chronic kidney disease (CKD) origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for 9 kidney disease entities that account for most of CKD worldwide. Our primary goal was to demonstrate the possibilities and potential on data analysis and integration to the nephrology community. Methods We integrated data from 5 publicly available studies and compared glomerular gene expression profiles of disease with that of controls from nontumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms, and conditions that we mitigated with a bespoke stringent procedure. Results We performed a global transcriptome-based delineation of different kidney disease entities, obtaining a transcriptomic diffusion map of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. We derived functional insights by inferring the activity of signaling pathways and transcription factors from the collected gene expression data and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating, for example, that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in rapidly progressive glomerulonephritis (RPGN) whereas not expressed in control kidney tissue. Furthermore, we found drug candidates by matching the signature on expression of drugs to that of the CKD entities, in particular, the Food and Drug Administration-approved drug nilotinib. Conclusion These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate further use, we provide our results as a free interactive Web application: https://saezlab.shinyapps.io/ckd_landscape/. However, because of the limitations of the data and the difficulties in its integration, any specific result should be considered with caution. Indeed, we consider this study rather an illustration of the value of functional genomics and integration of existing data.
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Affiliation(s)
- Ferenc Tajti
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Christoph Kuppe
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Asier Antoranz
- Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece.,Department of Testing Services, ProtATonce Ltd., Athens, Greece
| | - Mahmoud M Ibrahim
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Hyojin Kim
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
| | - Francesco Ceccarelli
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
| | - Christian H Holland
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.,Institute for Computational Biomedicine, Heidelberg University, Bioquant, Heidelberg, Germany
| | - Hannes Olauson
- Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Leonidas G Alexopoulos
- Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece.,Department of Testing Services, ProtATonce Ltd., Athens, Greece
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Julio Saez-Rodriguez
- Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.,Institute for Computational Biomedicine, Heidelberg University, Bioquant, Heidelberg, Germany
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24
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Omidian M, Mahmoudi M, Javanbakht MH, Eshraghian MR, Abshirini M, Daneshzad E, Hasani H, Alvandi E, Djalali M. Effects of vitamin D supplementation on circulatory YKL-40 and MCP-1 biomarkers associated with vascular diabetic complications: A randomized, placebo-controlled, double-blind clinical trial. Diabetes Metab Syndr 2019; 13:2873-2877. [PMID: 31425951 DOI: 10.1016/j.dsx.2019.07.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 07/29/2019] [Indexed: 11/26/2022]
Abstract
AIM Diabetic patients predispose to vascular diseases such as nephropathy, and retinopathy. Poor adherence to medical treatment and dietary recommendations in uncontrolled diabetes leads to vascular damages. Vitamin D has been extensively studied and found to be protective against diabetes mellitus. YKL-40 and Monocyte chemoattractant protein-1 (MCP-1) are considered to exert crucial role in diabetes and its complications. Therefore, this study was designed to investigate effects of vitamin D supplementation on serum levels of YKL-40 and MCP-1 involved in the development of diabetic complications. METHODS For 12 weeks, 48 type 2 diabetic patients enrolled in the trial and randomly were divided into two groups (n = 24 per group), receiving one of the following: 100 μg (4000 IU) vitamin D or placebo. Before and after intervention, serumYKL-40, MCP-1, insulin, IL-6, TNF-α, 25- (OH) vitamin D and HbA1c were measured. RESULTS Our results revealed that serum levels of 25 (OH) vitamin D significantly increased in vitamin D group (p < 0.001). Vitamin D supplementation also significantly reduced serum YKL-40 levels (-22.7 vs. -2.4 ng/ml; (p-value = 0.003)). There was a significant decline in MCP-1 concentration in intervention group at the end of the study (-45.7 vs. -0.9 pg/ml; (p = 0.001)). Furthermore, there was a significant decrease in IL-6, fasting insulin and HOMA-IR in intervention group after 3 months supplementation. CONCLUSIONS Daily vitamin D supplementation effectively reduced circulatory YKL-40 and MCP-1 levels in patients with type-2 diabetes and vitamin D deficiency. Vitamin D might contribute in reducing diabetic complications via modulating YKL-40 and MCP-1 signaling pathways.
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Affiliation(s)
- Mahsa Omidian
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoudi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Javanbakht
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Eshraghian
- Department of Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Abshirini
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Elnaz Daneshzad
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Hasani
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Alvandi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Djalali
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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25
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Abstract
PURPOSE OF REVIEW The purpose of this review is to provide a brief summary about the current state of knowledge regarding the circadian rhythm in the regulation of normal renal function. RECENT FINDINGS There is a lack of information regarding how the circadian clock mechanisms may contribute to the development of diabetic kidney disease. We discuss recent findings regarding mechanisms that are established in diabetic kidney disease and are known to be linked to the circadian clock as possible connections between these two areas. Here, we hypothesize various mechanisms that may provide a link between the clock mechanism and kidney disease in diabetes based on available data from humans and rodent models.
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Affiliation(s)
- Olanrewaju A Olaoye
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Box 100224, Gainesville, FL, 32610, USA
| | - Sarah H Masten
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Box 100224, Gainesville, FL, 32610, USA
| | - Rajesh Mohandas
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Box 100224, Gainesville, FL, 32610, USA
- North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - Michelle L Gumz
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Box 100224, Gainesville, FL, 32610, USA.
- North Florida/South Georgia Veterans Health System, Gainesville, FL, USA.
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
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26
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Saez-Rodriguez J, Rinschen MM, Floege J, Kramann R. Big science and big data in nephrology. Kidney Int 2019; 95:1326-1337. [PMID: 30982672 DOI: 10.1016/j.kint.2018.11.048] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 11/11/2018] [Accepted: 11/20/2018] [Indexed: 12/16/2022]
Abstract
There have been tremendous advances during the last decade in methods for large-scale, high-throughput data generation and in novel computational approaches to analyze these datasets. These advances have had a profound impact on biomedical research and clinical medicine. The field of genomics is rapidly developing toward single-cell analysis, and major advances in proteomics and metabolomics have been made in recent years. The developments on wearables and electronic health records are poised to change clinical trial design. This rise of 'big data' holds the promise to transform not only research progress, but also clinical decision making towards precision medicine. To have a true impact, it requires integrative and multi-disciplinary approaches that blend experimental, clinical and computational expertise across multiple institutions. Cancer research has been at the forefront of the progress in such large-scale initiatives, so-called 'big science,' with an emphasis on precision medicine, and various other areas are quickly catching up. Nephrology is arguably lagging behind, and hence these are exciting times to start (or redirect) a research career to leverage these developments in nephrology. In this review, we summarize advances in big data generation, computational analysis, and big science initiatives, with a special focus on applications to nephrology.
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Affiliation(s)
- Julio Saez-Rodriguez
- RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany; Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory and Heidelberg University, Heidelberg, Germany.
| | - Markus M Rinschen
- Department II of Internal Medicine, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Center for Mass Spectrometry and Metabolomics, The Scripps Research Institute, La Jolla, California, USA
| | - Jürgen Floege
- RWTH Aachen, Department of Nephrology and Clinical Immunology, Aachen, Germany
| | - Rafael Kramann
- RWTH Aachen, Department of Nephrology and Clinical Immunology, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.
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27
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Tian JS, Zhao L, Shen XL, Liu H, Qin XM. 1H NMR-based metabolomics approach to investigating the renal protective effects of Genipin in diabetic rats. Chin J Nat Med 2018; 16:261-270. [PMID: 29703326 DOI: 10.1016/s1875-5364(18)30056-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Indexed: 02/08/2023]
Abstract
Diabetic nephropathy is one of the various complications of diabetes mellitus, affecting patients for lifetime. Earlier studies have revealed that genipin can not only improve diabetes, but also induce cytotoxicity. Therefore, it is not clear which effect of genipin on kidneys occurs, when it is used in the treatment of diabetes. In the present study, we performed nuclear magnetic resonance (NMR)-based metabolomics analysis of urine and kidney tissue samples obtained from diabetic rats to explore the change of endogenous metabolites associated with diabetes and concomitant kidney disease. Nine significant differential metabolites that were closely related to renal function were screened. They were mainly related to three metabolic pathways: synthesis and degradation of ketone bodies, glycine, serine and threonine metabolism, and butanoate metabolism, which are involved in methylamine metabolism, energy metabolism and amino acid metabolism. In addition, after the intervention of genipin, the metabolic levels of all the metabolites tended to be normal, indicating a protective effect of genipin on kidneys. Our results may be helpful for understanding the antidiabetic effect of genipin.
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Affiliation(s)
- Jun-Sheng Tian
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China.
| | - Lei Zhao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
| | - Xiao-Li Shen
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China; College of Chemistry and Chemical Engineering of Shanxi University, Taiyuan 030006, China
| | - Huan Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China; College of Chemistry and Chemical Engineering of Shanxi University, Taiyuan 030006, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China.
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28
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Krochmal M, Cisek K, Filip S, Markoska K, Orange C, Zoidakis J, Gakiopoulou C, Spasovski G, Mischak H, Delles C, Vlahou A, Jankowski J. Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis. Sci Rep 2017; 7:9091. [PMID: 28831120 PMCID: PMC5567309 DOI: 10.1038/s41598-017-09393-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 07/26/2017] [Indexed: 12/19/2022] Open
Abstract
IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results.
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Affiliation(s)
- Magdalena Krochmal
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
- RWTH Aachen University Hospital, Institute for Molecular Cardiovascular Research, Aachen, Germany
| | | | - Szymon Filip
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
| | - Katerina Markoska
- Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia
| | - Clare Orange
- Department of Pathology, School of Medicine, University of Glasgow, Glasgow, UK
| | - Jerome Zoidakis
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
| | - Chara Gakiopoulou
- Pathology Department, National and Kapodistrian University of Athens, Athens, Greece
| | - Goce Spasovski
- Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, Hannover, Germany
- University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK
| | - Christian Delles
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - Antonia Vlahou
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece.
| | - Joachim Jankowski
- RWTH Aachen University Hospital, Institute for Molecular Cardiovascular Research, Aachen, Germany.
- University of Maastricht, CARIM School for Cardiovascular Diseases, Maastricht, Netherlands.
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29
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Malik S, Suchal K, Khan SI, Bhatia J, Kishore K, Dinda AK, Arya DS. Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am J Physiol Renal Physiol 2017; 313:F414-F422. [PMID: 28566504 DOI: 10.1152/ajprenal.00393.2016] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 05/12/2017] [Accepted: 05/26/2017] [Indexed: 12/23/2022] Open
Abstract
Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti-inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5-20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-β1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-α, IL-6, and NF-κB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway.
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Affiliation(s)
- Salma Malik
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
| | - Kapil Suchal
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
| | - Sana Irfan Khan
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
| | - Jagriti Bhatia
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
| | - Kamal Kishore
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
| | - Amit Kumar Dinda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Dharamvir Singh Arya
- Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi, India; and
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30
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Rinschen MM, Grahammer F, Hoppe AK, Kohli P, Hagmann H, Kretz O, Bertsch S, Höhne M, Göbel H, Bartram MP, Gandhirajan RK, Krüger M, Brinkkoetter PT, Huber TB, Kann M, Wickström SA, Benzing T, Schermer B. YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal 2017; 10:10/474/eaaf8165. [PMID: 28400537 DOI: 10.1126/scisignal.aaf8165] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Podocytes are terminally differentiated cells of the kidney filtration barrier. They are subjected to physiological filtration pressure and considerable mechanical strain, which can be further increased in various kidney diseases. When injury causes cytoskeletal reorganization and morphological alterations of these cells, the filtration barrier may become compromised and allow proteins to leak into the urine (a condition called proteinuria). Using time-resolved proteomics, we showed that podocyte injury stimulated the activity of the transcriptional coactivator YAP and the expression of YAP target genes in a rat model of glomerular disease before the development of proteinuria. Although the activities of YAP and its ortholog TAZ are activated by mechanical stress in most cell types, injury reduced YAP and TAZ activity in cultured human and mouse podocyte cell lines grown on stiff substrates. Culturing these cells on soft matrix or inhibiting stress fiber formation recapitulated the damage-induced YAP up-regulation observed in vivo, indicating a mechanotransduction-dependent mechanism of YAP activation in podocytes. YAP overexpression in cultured podocytes increased the abundance of extracellular matrix-related proteins that can contribute to fibrosis. YAP activity was increased in mouse models of diabetic nephropathy, and the YAP target CTGF was highly expressed in renal biopsies from glomerular disease patients. Although overexpression of human YAP in mice induced mild proteinuria, pharmacological inhibition of the interaction between YAP and its partner TEAD in rats ameliorated glomerular disease and reduced damage-induced mechanosignaling in the glomeruli. Thus, perturbation of YAP-dependent mechanosignaling is a potential therapeutic target for treating some glomerular diseases.
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Affiliation(s)
- Markus M Rinschen
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.,Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Florian Grahammer
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.,III. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ann-Kathrin Hoppe
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Priyanka Kohli
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany
| | - Henning Hagmann
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Oliver Kretz
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.,III. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sabine Bertsch
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Martin Höhne
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.,Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Heike Göbel
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Malte P Bartram
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | | | - Marcus Krüger
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany
| | - Paul-Thomas Brinkkoetter
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Tobias B Huber
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.,III. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.,Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Martin Kann
- Department of Internal Medicine II, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Sara A Wickström
- Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.,Skin Homeostasis and Ageing, Paul Gerson Unna Research Group, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Thomas Benzing
- Department of Internal Medicine II, University of Cologne, Cologne, Germany. .,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.,Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Bernhard Schermer
- Department of Internal Medicine II, University of Cologne, Cologne, Germany. .,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.,Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
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31
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Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal Physiol 2017; 312:F716-F731. [PMID: 27558558 PMCID: PMC6109808 DOI: 10.1152/ajprenal.00314.2016] [Citation(s) in RCA: 191] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/16/2016] [Indexed: 01/10/2023] Open
Abstract
Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.
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Affiliation(s)
- Raimund Pichler
- Division of Nephrology, University of Washington, Seattle, Washington;
| | - Maryam Afkarian
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
| | - Brad P Dieter
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
| | - Katherine R Tuttle
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
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32
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Mohabbulla Mohib M, Fazla Rabby S, Paran TZ, Mehedee Hasan M, Ahmed I, Hasan N, Abu Taher Sagor M, Mohiuddin S. Protective role of green tea on diabetic nephropathy—A review. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/23312025.2016.1248166] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Md. Mohabbulla Mohib
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - S.M. Fazla Rabby
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Tasfiq Zaman Paran
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md. Mehedee Hasan
- Department of Pharmacy, State University of Bangladesh, Dhaka 1205, Bangladesh
| | - Iqbal Ahmed
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Nahid Hasan
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md. Abu Taher Sagor
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Sarif Mohiuddin
- Department of Anatomy, Pioneer Dental College and Hospital, Dhaka 1229, Bangladesh
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33
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miR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy. Nat Commun 2016; 7:12076. [PMID: 27350436 PMCID: PMC4931323 DOI: 10.1038/ncomms12076] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 05/26/2016] [Indexed: 01/15/2023] Open
Abstract
How the kidney responds to the metabolic cues from the environment remains a central question in kidney research. This question is particularly relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. Here, we show that miR-93 is a critical metabolic/epigenetic switch in the diabetic milieu linking the metabolic state to chromatin remodelling. Mice with inducible overexpression of a miR-93 transgene exclusively in podocytes exhibit significant improvements in key features of DN. We identify miR-93 as a regulator of nucleosomal dynamics in podocytes. miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10. These findings implicate a central role for miR-93 in high glucose-induced chromatin remodelling in the kidney, and provide evidence for a previously unrecognized role for Msk2 as a target for DN therapy. Podocyte injury is central to kidney dysfunction in diabetic nephropathy. Here the authors show that Msk2 is a target of miR-93 and this interaction mediates pathogenic chromatin remodelling in diabetic nephropathy.
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Sugar T, Wassenhove-McCarthy DJ, Orr AW, Green J, van Kuppevelt TH, McCarthy KJ. N-sulfation of heparan sulfate is critical for syndecan-4-mediated podocyte cell-matrix interactions. Am J Physiol Renal Physiol 2016; 310:F1123-35. [PMID: 26936875 PMCID: PMC5002056 DOI: 10.1152/ajprenal.00603.2015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 02/26/2016] [Indexed: 12/23/2022] Open
Abstract
Previous research has shown that podocytes unable to assemble heparan sulfate on cell surface proteoglycan core proteins have compromised cell-matrix interactions. This report further explores the role of N-sulfation of intact heparan chains in podocyte-matrix interactions. For the purposes of this study, a murine model in which the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1) was specifically deleted in podocytes and immortalized podocyte cell lines lacking NDST1 were developed and used to explore the effects of such a mutation on podocyte behavior in vitro. NDST1 is a bifunctional enzyme, ultimately responsible for N-sulfation of heparan glycosaminoglycans produced by cells. Immunostaining of glomeruli from mice whose podocytes were null for Ndst1 (Ndst1(-/-)) showed a disrupted pattern of localization for the cell surface proteoglycan, syndecan-4, and for α-actinin-4 compared with controls. The pattern of immunostaining for synaptopodin and nephrin did not show as significant alterations. In vitro studies showed that Ndst1(-/-) podocytes attached, spread, and migrated less efficiently than Ndst1(+/+) podocytes. Immunostaining in vitro for several markers for molecules involved in cell-matrix interactions showed that Ndst1(-/-) cells had decreased clustering of syndecan-4 and decreased recruitment of protein kinase-Cα, α-actinin-4, vinculin, and phospho-focal adhesion kinase to focal adhesions. Total intracellular phospho-focal adhesion kinase was decreased in Ndst1(-/-) compared with Ndst1(+/+) cells. A significant decrease in the abundance of activated integrin α5β1 on the cell surface of Ndst1(-/-) cells compared with Ndst1(+/+) cells was observed. These results serve to highlight the critical role of heparan sulfate N-sulfation in facilitating normal podocyte-matrix interactions.
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Affiliation(s)
- Terrel Sugar
- Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, Louisiana
| | | | - A Wayne Orr
- Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana; and
| | - Jonette Green
- Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana; and
| | - Toin H van Kuppevelt
- Department of Biochemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Kevin J McCarthy
- Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, Louisiana; Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana; and
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Papadopoulos T, Krochmal M, Cisek K, Fernandes M, Husi H, Stevens R, Bascands JL, Schanstra JP, Klein J. Omics databases on kidney disease: where they can be found and how to benefit from them. Clin Kidney J 2016; 9:343-52. [PMID: 27274817 PMCID: PMC4886900 DOI: 10.1093/ckj/sfv155] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
In the recent decades, the evolution of omics technologies has led to advances in all biological fields, creating a demand for effective storage, management and exchange of rapidly generated data and research discoveries. To address this need, the development of databases of experimental outputs has become a common part of scientific practice in order to serve as knowledge sources and data-sharing platforms, providing information about genes, transcripts, proteins or metabolites. In this review, we present omics databases available currently, with a special focus on their application in kidney research and possibly in clinical practice. Databases are divided into two categories: general databases with a broad information scope and kidney-specific databases distinctively concentrated on kidney pathologies. In research, databases can be used as a rich source of information about pathophysiological mechanisms and molecular targets. In the future, databases will support clinicians with their decisions, providing better and faster diagnoses and setting the direction towards more preventive, personalized medicine. We also provide a test case demonstrating the potential of biological databases in comparing multi-omics datasets and generating new hypotheses to answer a critical and common diagnostic problem in nephrology practice. In the future, employment of databases combined with data integration and data mining should provide powerful insights into unlocking the mysteries of kidney disease, leading to a potential impact on pharmacological intervention and therapeutic disease management.
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Affiliation(s)
- Theofilos Papadopoulos
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Magdalena Krochmal
- Biotechnology Division, Biomedical Research Foundation Academy of Athens, Athens, Greece; Institute for Molecular Cardiovascular Research, Universitätsklinikum RWTH Aachen, Aachen, Germany
| | | | - Marco Fernandes
- BHF Glasgow Cardiovascular Research Centre , University of Glasgow , Glasgow , UK
| | - Holger Husi
- BHF Glasgow Cardiovascular Research Centre , University of Glasgow , Glasgow , UK
| | - Robert Stevens
- School of Computer Science , University of Manchester , Manchester , UK
| | - Jean-Loup Bascands
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Joost P Schanstra
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Julie Klein
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
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Shahzad K, Bock F, Al-Dabet MM, Gadi I, Kohli S, Nazir S, Ghosh S, Ranjan S, Wang H, Madhusudhan T, Nawroth PP, Isermann B. Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy. J Am Soc Nephrol 2016; 27:2270-5. [PMID: 26832955 DOI: 10.1681/asn.2015060676] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 12/12/2015] [Indexed: 12/14/2022] Open
Abstract
Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1β), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucose-stressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.
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Affiliation(s)
- Khurrum Shahzad
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Molecular Genetics, University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan
| | - Fabian Bock
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany
| | - Moh'd Mohanad Al-Dabet
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Ihsan Gadi
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Shrey Kohli
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Sumra Nazir
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Sanchita Ghosh
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Satish Ranjan
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Hongjie Wang
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and
| | - Thati Madhusudhan
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany
| | - Peter P Nawroth
- Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany
| | - Berend Isermann
- Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
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Emerging role of liver X receptors in cardiac pathophysiology and heart failure. Basic Res Cardiol 2015; 111:3. [PMID: 26611207 PMCID: PMC4661180 DOI: 10.1007/s00395-015-0520-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/03/2015] [Indexed: 01/09/2023]
Abstract
Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.
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Nozako M, Koyama T, Nagano C, Sato M, Matsumoto S, Mitani K, Yasufuku R, Kohashi M, Yoshikawa T. An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats. PLoS One 2015; 10:e0143979. [PMID: 26606054 PMCID: PMC4659596 DOI: 10.1371/journal.pone.0143979] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/11/2015] [Indexed: 11/18/2022] Open
Abstract
Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment.
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Affiliation(s)
- Masanori Nozako
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Takashi Koyama
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Chifumi Nagano
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Makoto Sato
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Satoshi Matsumoto
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Kiminobu Mitani
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Reiko Yasufuku
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Masayuki Kohashi
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Tomohiro Yoshikawa
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- * E-mail:
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Cisek K, Krochmal M, Klein J, Mischak H. The application of multi-omics and systems biology to identify therapeutic targets in chronic kidney disease. Nephrol Dial Transplant 2015; 31:2003-2011. [DOI: 10.1093/ndt/gfv364] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/18/2015] [Indexed: 12/17/2022] Open
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Wei F, Cai C, Feng S, Lv J, Li S, Chang B, Zhang H, Shi W, Han H, Ling C, Yu P, Chen Y, Sun N, Tian J, Jiao H, Yang F, Li M, Wang Y, Zou L, Su L, Li J, Li R, Qiu H, Shi J, Liu S, Chang M, Lin J, Chen L, Li WD. TOX and CDKN2A/B Gene Polymorphisms Are Associated with Type 2 Diabetes in Han Chinese. Sci Rep 2015; 5:11900. [PMID: 26139146 PMCID: PMC4650661 DOI: 10.1038/srep11900] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 06/08/2015] [Indexed: 12/27/2022] Open
Abstract
To study associations between type 2 diabetes (T2DM) candidate genes and microvascular complications of diabetes (MVCDs), we performed case-control association studies for both T2DM and MVCDs in Han Chinese subjects. We recruited 1,939 unrelated Han Chinese T2DM patients and 918 individuals with normal blood glucose levels as nondiabetic controls. Among T2DM patients, 1116 have MVCDs, 266 have a history of T2DM of >10 years but never developed MVCDs. Eighty-two single-nucleotide polymorphisms (SNPs) in 54 candidate genes were genotyped. Discrete association studies were performed by the PLINK program for T2DM and MVCDs. Significant associations were found among candidate gene SNPs and T2DM, including rs1526167 of the TOX gene (allele A, P = 2.85 × 10−9, OR = 1.44). The SNP rs10811661 of the CDKN2A/B gene was also associated with T2DM (allele T, P = 4.09 × 10−7, OR = 1.36). When we used control patients with >10 years of T2DM history without MVCD, we found that the G allele of SNP rs1526167 of the TOX gene was associated with MVCD (nominal P = 4.33 × 10−4). In our study, significant associations were found between TOX and CDKN2A/B gene SNPs and T2DM. The TOX polymorphism might account for the higher risk of T2DM and the lower risk of MVCDs in the Han Chinese population.
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Affiliation(s)
- Fengjiang Wei
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Chunyou Cai
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Shuzhi Feng
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Jia Lv
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Shen Li
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Baocheng Chang
- Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Hong Zhang
- Eye Hospital, Tianjin Medical University, Tianjin, 300384, China
| | - Wentao Shi
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Hongling Han
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Chao Ling
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ping Yu
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yongjun Chen
- Eye Hospital, Tianjin Medical University, Tianjin, 300384, China
| | - Ning Sun
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Jianli Tian
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Hongxiao Jiao
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Fuhua Yang
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Mingshan Li
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yuhua Wang
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Lei Zou
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Long Su
- Eye Hospital, Tianjin Medical University, Tianjin, 300384, China
| | - Jingbo Li
- Tianjin People's Hospital, Department of Endocrinology, Tianjin, 300191, China
| | - Ran Li
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Huina Qiu
- Tianjin People's Hospital, Department of Endocrinology, Tianjin, 300191, China
| | - Jingmin Shi
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Shiying Liu
- Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Mingqin Chang
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Jingna Lin
- Tianjin People's Hospital, Department of Endocrinology, Tianjin, 300191, China
| | - Liming Chen
- Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Wei-Dong Li
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
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Dabhi B, Mistry KN. Oxidative stress and its association with TNF-α-308 G/C and IL-1α-889 C/T gene polymorphisms in patients with diabetes and diabetic nephropathy. Gene 2015; 562:197-202. [PMID: 25732517 DOI: 10.1016/j.gene.2015.02.069] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/16/2015] [Accepted: 02/25/2015] [Indexed: 11/24/2022]
Abstract
Diabetic nephropathy is one of the major complications of type 2 diabetes and it is currently the leading cause of end-stage renal disease. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species might be a primary source. This study was conducted in four groups in West Indian population: control (235), type 2 diabetes (DM) (214), nephropathy with diabetes (DN) (188) and nephropathy without diabetes (NDN) (196). Oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), superoxide dismutase and catalase were measured in all the groups. TNF-α-308 G/C and IL-1α-889 C/T polymorphisms were analyzed using PCR-RFLP method. Correlations between genotype frequency and the level of oxidative stress markers were examined. MDA was significantly increased in the patient group in comparison to control group. GSH and SOD were significantly decreased in the patient group in comparison to control group. There was no significant difference observed in genotype frequency of TNF-α in the patient group compared with control group. IL-1α-889 C/T polymorphism may be associated with diabetic nephropathy. Moreover there was no association of TNF-α-308 G/C polymorphism with diabetic nephropathy in West Indian population. The higher serum levels of oxidative stress markers in diabetic patients with nephropathy suggest the possible role of oxidative stress.
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Affiliation(s)
- Brijesh Dabhi
- Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences (ARIBAS), New Vallabh Vidyanagar, Affiliated to Sardar Patel University, Anand 388121, Gujarat, India
| | - Kinnari N Mistry
- Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences (ARIBAS), New Vallabh Vidyanagar, Affiliated to Sardar Patel University, Anand 388121, Gujarat, India.
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Buffon MP, Sortica DA, Gerchman F, Crispim D, Canani LH. FRMD3 gene: its role in diabetic kidney disease. A narrative review. Diabetol Metab Syndr 2015; 7:118. [PMID: 26719775 PMCID: PMC4696171 DOI: 10.1186/s13098-015-0114-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 12/19/2015] [Indexed: 01/15/2023] Open
Abstract
Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus, which is considered a worldwide epidemic. Several studies have been developed in order to elucidate possible genetic factors involved in this disease. The FRMD3 gene, a strong candidate selected from genome wide association studies (GWAS), encodes the structural protein 4.1O involved in maintaining cell shape and integrity. Some single nucleotide polymorphisms (SNPs) located in FRMD3 have been associated with DKD in different ethnicities. However, despite these findings, the matter is still controversial. The aim of this narrative review is to summarize the evidence regarding the role of FRMD3 in DKD.
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Affiliation(s)
- Marjoriê Piuco Buffon
- />Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, RS 90035-003 Brazil
- />Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
- />Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
| | - Denise Alves Sortica
- />Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, RS 90035-003 Brazil
- />Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
- />Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
| | - Fernando Gerchman
- />Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, RS 90035-003 Brazil
- />Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
- />Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
| | - Daisy Crispim
- />Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, RS 90035-003 Brazil
- />Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
| | - Luís Henrique Canani
- />Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, RS 90035-003 Brazil
- />Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
- />Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
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Donate-Correa J, Martín-Núñez E, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res 2015; 2015:948417. [PMID: 25785280 PMCID: PMC4345080 DOI: 10.1155/2015/948417] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/17/2015] [Accepted: 01/31/2015] [Indexed: 12/12/2022] Open
Abstract
Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- *Javier Donate-Correa: and
| | - Ernesto Martín-Núñez
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Mercedes Muros-de-Fuentes
- Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Juan F. Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Nephrology Service, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- *Juan F. Navarro-González:
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García-García PM, Getino-Melián MA, Domínguez-Pimentel V, Navarro-González JF. Inflammation in diabetic kidney disease. World J Diabetes 2014; 5:431-443. [PMID: 25126391 PMCID: PMC4127580 DOI: 10.4239/wjd.v5.i4.431] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 02/24/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.
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Discovery of new glomerular disease-relevant genes by translational profiling of podocytes in vivo. Kidney Int 2014; 86:1116-29. [PMID: 24940801 PMCID: PMC4245460 DOI: 10.1038/ki.2014.204] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 04/08/2014] [Accepted: 04/24/2014] [Indexed: 12/25/2022]
Abstract
Identifying new biomarkers and therapeutic targets for podocytopathies such as focal segmental glomerulosclerosis (FSGS) requires a detailed analysis of transcriptional changes in podocytes over the course of disease. Here we used translating ribosome affinity purification (TRAP) to isolate and profile podocyte-specific mRNA in two different models of FSGS. Expressed eGFP-tagged ribosomal protein L10a in podocytes under the control of the Collagen-1α1 promoter enabled podocyte-specific mRNA isolation in a one-step process over the course of disease. This TRAP protocol robustly enriched known podocyte-specific mRNAs. We crossed col1α1-L10a mice with the actn4−/− and actn4+/K256E models of FSGS and analyzed podocyte transcriptional profiles at 2, 6 and 44 weeks of age. Two upregulated podocyte genes in murine FSGS (CXCL1 and DMPK) were found to be upregulated at the protein level in biopsies from patients with FSGS, validating this approach. There was no dilution of podocyte-specific transcripts during disease. These are the first podocyte-specific RNA expression datasets during aging and in two models of FSGS. This approach identified new podocyte proteins that are upregulated in FSGS and help define novel biomarkers and therapeutic targets for human glomerular disease.
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Martini S, Nair V, Keller BJ, Eichinger F, Hawkins JJ, Randolph A, Böger CA, Gadegbeku CA, Fox CS, Cohen CD, Kretzler M. Integrative biology identifies shared transcriptional networks in CKD. J Am Soc Nephrol 2014; 25:2559-72. [PMID: 24925724 DOI: 10.1681/asn.2013080906] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFR-associated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation- and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases.
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Affiliation(s)
- Sebastian Martini
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Viji Nair
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Benjamin J Keller
- Department of Computer Science, Eastern Michigan University, Ypsilanti, Michigan
| | - Felix Eichinger
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Jennifer J Hawkins
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Ann Randolph
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Carsten A Böger
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Crystal A Gadegbeku
- Department of Medicine, Section of Nephrology and Kidney Transplantation, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Caroline S Fox
- Division of Intramural Research and Laboratory for Population and Metabolic Health, National Heart, Lung, and Blood Institute, Framingham, Massachusetts; Department of Endocrinology, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Clemens D Cohen
- Institute of Physiology, University of Zürich, Zürich, Switzerland
| | - Matthias Kretzler
- Departments of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan;
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Fan Y, Wei C, Xiao W, Zhang W, Wang N, Chuang PY, He JC. Temporal profile of the renal transcriptome of HIV-1 transgenic mice during disease progression. PLoS One 2014; 9:e93019. [PMID: 24667548 PMCID: PMC3965528 DOI: 10.1371/journal.pone.0093019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/27/2014] [Indexed: 01/15/2023] Open
Abstract
Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets.
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Affiliation(s)
- Ying Fan
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Wenzhen Xiao
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Niansong Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Peter Y. Chuang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail:
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Patel M, Wang XX, Magomedova L, John R, Rasheed A, Santamaria H, Wang W, Tsai R, Qiu L, Orellana A, Advani A, Levi M, Cummins CL. Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice. Diabetologia 2014; 57:435-46. [PMID: 24201575 DOI: 10.1007/s00125-013-3095-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 10/01/2013] [Indexed: 10/26/2022]
Abstract
AIMS/HYPOTHESIS Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes. METHODS Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β (+/+) (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β (-/-) mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N,N-dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. RESULTS Even in the absence of diabetes, Lxrα/β (-/-) mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β (+/+) mice. When challenged with diabetes, Lxrα/β (-/-) mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. CONCLUSIONS/INTERPRETATION These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.
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Affiliation(s)
- Monika Patel
- Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, ON, M5S 3M2, Canada
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Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 2013; 55:561-72. [PMID: 24371263 DOI: 10.1194/jlr.p040501] [Citation(s) in RCA: 437] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid β-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis.
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Affiliation(s)
- Michal Herman-Edelstein
- Felsenstein Medical Research Center, and Departments of Nephrology Rabin Medical Center, Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel
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A meta-analysis of expression signatures in glomerular disease. Kidney Int 2013; 84:591-9. [DOI: 10.1038/ki.2013.169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 02/02/2013] [Accepted: 03/01/2013] [Indexed: 12/19/2022]
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