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1
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Bui AP, Pham TTM, Kim M, Park JH, Kim JI, Seo JH, Jung J, Kim JY, Ha E. GLDC alleviates cisplatin-induced apoptosis, cellular senescence, and production of reactive oxygen species via regulating UCP1 in the kidney. Life Sci 2025; 368:123502. [PMID: 40010632 DOI: 10.1016/j.lfs.2025.123502] [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: 12/24/2024] [Revised: 02/08/2025] [Accepted: 02/18/2025] [Indexed: 02/28/2025]
Abstract
AIMS Glycine decarboxylase (GLDC) is a mitochondrial enzyme that mediates the degradation of glycine as part of the glycine cleavage system. Although GLDC expression in the kidney is second highest next to the liver, very little is known as to the role of GLDC in the kidney. Thus, this study aimed to elucidate the role of GLDC in the kidney. MATERIALS AND METHODS HK-2 renal proximal tubular cells with GLDC overexpression and knockdown were established to investigate function of GLDC in cells treated with cisplatin (CP). For in vivo experiments, C57BL/6J mice were used in a CP-induced AKI model, with and without treatment with (aminooxy)acetic acid (AOAA), a GLDC inhibitor. KEY FINDINGS We found that GLDC overexpression attenuated CP-induced apoptosis, cellular senescence and production of reactive oxygen species (ROS) in HK2 cells, while GLDC knockdown aggravated these effects. Moreover, GLDC overexpression stimulated proliferation of HK-2 cells, while GLDC knockdown attenuated cell growth. Mechanistically, we found that effects of GLDC are mediated via modulating mitochondrial uncoupling protein 1 (UCP1). GLDC overexpression increased UCP1, while GLDC knockdown decreased UCP1. Knockdown of UCP1 reversed GLDC-mediated attenuation of CP-induced cellular senescence and ROS production. Treatment of AOAA into acute kidney injury (AKI)-induced mice aggravated AKI injury, increasing biomarkers, fibrosis and senescence associated-β-galactosidase staining. SIGNIFICANCE GLDC protects CP-induced apoptosis, cellular senescence, and ROS production in proximal tubular cells via a UCP-mediated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of cisplatin-induced AKI.
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Affiliation(s)
- Anh Phuc Bui
- Department of Biochemistry, School of Medicine, Keimyung University, Republic of Korea
| | - Thi Tuyet Mai Pham
- Department of Biochemistry, School of Medicine, Keimyung University, Republic of Korea
| | - Mikyung Kim
- Department of Biochemistry, School of Medicine, Keimyung University, Republic of Korea
| | - Jae-Hyung Park
- Department of Physiology, School of Medicine, Keimyung University, Republic of Korea
| | - Jee In Kim
- Department of Molecular Medicine, School of Medicine, Keimyung University, Republic of Korea
| | - Ji Hae Seo
- Department of Biochemistry, School of Medicine, Keimyung University, Republic of Korea
| | - Jeeyeon Jung
- Clinical Research Division, Korea Institute of Oriental Medicine, Republic of Korea.
| | - Jin Young Kim
- Division of Haematology and Oncology, Department of Internal Medicine, School of Medicine, Keimyung University, Republic of Korea.
| | - Eunyoung Ha
- Department of Biochemistry, School of Medicine, Keimyung University, Republic of Korea.
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2
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Hu L, Jiao C, Gu H, Zhu Z, Liang M. Identification and validation of leukemia inhibitory factor as a protective factor in ischemic acute kidney injury. Am J Med Sci 2025; 369:524-536. [PMID: 39313116 DOI: 10.1016/j.amjms.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 09/20/2024] [Accepted: 09/20/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) is a common pathophysiological mechanism of acute kidney injury (AKI). There is an urgent need for a more comprehensive analysis of its underlying mechanisms. MATERIALS AND METHODS The RNA-sequencing dataset GSE153625 was used to examine differentially expressed genes (DEGs) of kidney tissues in IRI-AKI mice compared with sham mice. We used 10 algorithms provided by cytohubba plugin and four external datasets (GSE192532, GSE52004, GSE98622, and GSE185383) to screen for hub genes. The IRI-AKI mouse model with different reperfusion times was established to validate the expression of hub gene in the kidneys. HK-2 cells were cultured in vitro under hypoxia/reoxygenation (H/R) conditions, via transfection with si-LIF or supplementation with the LIF protein to explore the function of the LIF gene. RESULTS We screened a total of 1,540 DEGs in the IRI group compared with the sham group and identified that the LIF hub gene may play potential roles in IRI-AKI. LIF was markedly upregulated in the kidney tissues of IRI-AKI mice, as well as in HK-2 cells grown under H/R conditions. The knockdown of LIF aggravated apoptosis and oxidative stress (OS) injury under H/R conditions. Administration of the LIF protein rescued the effects of si-LIF, alleviating cellular apoptosis and OS. CONCLUSION These findings indicate an important role of the LIF gene in term of regulating apoptosis and OS in the early phases of IRI-AKI. Targeting LIF may therefore represent a promising therapeutic strategy for IRI-AKI.
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Affiliation(s)
- Lemei Hu
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Panfu Road, Guangzhou, Guangdong 510000, China
| | - Chen Jiao
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Panfu Road, Guangzhou, Guangdong 510000, China
| | - Haiyu Gu
- Department of Emergency Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Zhigang Zhu
- Division of Hematology & Oncology, Department of Geriatrics, Second Affiliated Hospital, Guangzhou First People's Hospital, College of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Ming Liang
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Panfu Road, Guangzhou, Guangdong 510000, China.
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3
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Mon-Wei Yu S, Choi JY, Kady J, De Cos M, Wong JS, King E, Younis N, Al Rahy N, Al Chaar S, Djebli H, Eskandari S, Samuel S, Merhej T, Sukumar N, Lin JR, Chen JY, Xu Y, Santagata S, Weins A, Yeung M, Cravedi P, Campbell KN, Lemos D, Bonventre JV, Brehm M, Azzi J. Transplantation of human kidney organoids elicited a robust allogeneic response in a humanized mouse model. Kidney Int 2025:S0085-2538(25)00255-8. [PMID: 40127865 DOI: 10.1016/j.kint.2025.02.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/03/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025]
Abstract
Human kidney organoids derived from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) have become novel tools for studying various kidney pathologies. Here, we transplanted ESC-derived kidney organoids into humanized mice with a mature human adaptive immune system developed through thymic education. As judged by histology and immunophenotyping, the transplanted HLA-mismatched kidney organoids trigged a robust alloimmune response, characterized by a dense immune cell infiltrate and enhanced memory T cell phenotype in the allograft 30 days post-transplantation. Multiplexed immunofluorescence revealed expression of functional markers of various immune cell infiltrates in response to organoid allografts, mimicking the T cell-mediated rejection process in humans. This validated our model as a novel platform to study various therapeutic strategies to control alloimmunity. Splenocytes isolated from organoid-transplanted hosts showed an alloantigen-specific memory response against 2D kidney organoids ex vivo. Overall, our study indicates that transplanting kidney organoids in humanized mice may be a valuable tool for studying human allogeneic immunity.
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Affiliation(s)
- Samuel Mon-Wei Yu
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA; Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John Yongjoon Choi
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jamie Kady
- University of Massachusetts, Worcester, Massachusetts, USA
| | - Marina De Cos
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA
| | - Jenny S Wong
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA
| | - Emily King
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA
| | - Nour Younis
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nadim Al Rahy
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Doctoral School of Science and Technology, Lebanese University, Beirut, Lebanon
| | - Soltan Al Chaar
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Doctoral School of Science and Technology, Lebanese University, Beirut, Lebanon
| | - Houda Djebli
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Institute of Biological Science, Faculty of Medical Sciences, Mohammed VI Polytechnic University, Benguerir, Morocco
| | - Siawosh Eskandari
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Stephen Samuel
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tamara Merhej
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nivedha Sukumar
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Northeastern University, Boston, Massachusetts, USA
| | - Jia-Ren Lin
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Jia-Yun Chen
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Yilin Xu
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Sandro Santagata
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Astrid Weins
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Melissa Yeung
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paolo Cravedi
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA
| | - Kirk N Campbell
- Department of Medicine, Nephrology Division, Mount Sinai Hospital, New York, New York, USA
| | - Dario Lemos
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, USA
| | - Joseph V Bonventre
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, USA; Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Michael Brehm
- University of Massachusetts, Worcester, Massachusetts, USA
| | - Jamil Azzi
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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4
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Abousaad S, Ahmed F, Abouzeid A, Adhiambo C, Ongeri E. Meprin β activity modulates cellular proliferation via trans-signaling IL-6-mediated AKT/ERK pathway in IR-induced kidney injury. RESEARCH SQUARE 2025:rs.3.rs-5901359. [PMID: 39975921 PMCID: PMC11838750 DOI: 10.21203/rs.3.rs-5901359/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Inflammation plays a central role in the progression of kidney injury induced by ischemia/reperfusion (IR). Meprin metalloproteinases have been implicated in the pathophysiology of IR-induced kidney injury. Existing data from in vitro and in vivo studies show that meprins modulate interleukin-6 (IL-6)-mediated inflammation via proteolytic processing of IL-6 and its receptor. IL-6 trans-signaling induces proliferation through either MAPK/ERK or PI3K/AKT pathway or in crosstalk with AKT/ERK. We previously showed that meprin β modulates cellular survival (BCL-2) through IL-6/JAK/STAT signaling pathway in IR-induced kidney injury. However, it's not known how meprin β modulation of the IL-6 signaling pathway impacts the cellular proliferation in IR-induced acute kidney injury. The goal of the current study was to determine how meprin β modulation of the IL-6 signaling pathway impacts downstream cellular proliferation in IR-induced kidney injury. We used the unilateral IR as a model of renal inflammation in wild-type (WT) and meprin β knockout (βKO) mice, with the contralateral kidneys serving as controls. The mice were sacrificed at 96 h post-IR, and kidney tissue processed for evaluation by RT-PCR and immunohistochemistry. Statistical analysis utilized two-way ANOVA. RT-PCR data showed a significant increase in mRNA levels for IL-6 and proliferating cell nuclear antigen (PCNA) in WT and βKO mice at 96 h-post IR when compared to WT control kidneys. However, the baseline mRNA levels for PCNA were significantly higher in βKO when compared to WT kidneys. Immunohistochemical data showed significant increases in IL-6, PCNA, p-AKT and p-ERK in select tubules in both genotypes at 96 h post-IR when compared to control kidneys for each genotype. Data from immunofluorescence counterstaining of kidney tissues revealed that at 96 hours post-IR, IL-6, PCNA, p-AKT, and p-ERK were primarily expressed in meprin β-expressing proximal tubules (PTs), where meprins are abundantly present. However, high levels of IL-6 were also present in the lumen of PTs and DTs from WT and βKO kidneys at 96 h post-IR, suggesting increased release/shedding into filtrate and subsequently into urine. In conclusion, this study highlights the role of meprin β activity in regulating cellular proliferation through PCNA regulation, driven by the IL-6-mediated AKT/ERK signaling pathway during the recovery phase following IR-induced kidney injury.
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Affiliation(s)
| | - Faihaa Ahmed
- the College of Veterinary Medicine, North Carolina State University
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5
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Janosevic D, De Luca T, Eadon MT. The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:7-22. [PMID: 39332674 PMCID: PMC11686451 DOI: 10.1016/j.ajpath.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/29/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024]
Abstract
Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.
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Affiliation(s)
- Danielle Janosevic
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Thomas De Luca
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Michael T Eadon
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana.
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6
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Lee BJ, Flood TR, Russell SL, McCormick JJ, Fujii N, Kenny GP. Impacts of age, type 2 diabetes, and hypertension on circulating neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 after prolonged work in the heat in men. Eur J Appl Physiol 2024; 124:2923-2939. [PMID: 38753017 DOI: 10.1007/s00421-024-05505-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 05/05/2024] [Indexed: 10/11/2024]
Abstract
PURPOSE Prolonged work in the heat increases the risk of acute kidney injury (AKI) in young men. Whether aging and age-associated chronic disease may exacerbate the risk of AKI remains unclear. METHODS We evaluated plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum kidney injury molecule-1 (KIM1) before and after 180 min of moderate-intensity work (200 W/m2) in temperate (wet-bulb globe temperature [WBGT] 16 °C) and hot (32 °C) environments in healthy young (n = 13, 22 years) and older men (n = 12, 59 years), and older men with type 2 diabetes (T2D; n = 9, 60 years) or hypertension (HTN; n = 9, 60 years). RESULTS There were no changes in NGAL or KIM1 concentrations following prolonged work in temperate conditions in any group. Despite a similar work tolerance, the relative change in NGAL was greater in the older group when compared to the young group following exercise in the hot condition (mean difference + 82 ng/mL; p < 0.001). Baseline concentrations of KIM1 were ~ 22 pg/mL higher in the older relative to young group, increasing by ~ 10 pg/mL in each group after exercise in the heat (both p ≤ 0.03). Despite a reduced work tolerance in the heat in older men with T2D (120 ± 40 min) and HTN (108 ± 42 min), elevations in NGAL and KIM1 were similar to their healthy counterparts. CONCLUSION Age may be associated with greater renal stress following prolonged work in the heat. The similar biomarker responses in T2D and HTN compared to healthy older men, alongside reduced exercise tolerance in the heat, suggest these individuals may exhibit greater vulnerability to heat-induced AKI if work is prolonged.
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Affiliation(s)
- Ben J Lee
- Occupational and Environmental Physiology Group, Centre for Physical Activity, Sport and Exercise Science, Coventry University, Coventry, UK
| | - Tessa R Flood
- Institute of Sport, Manchester Metropolitan University, Manchester, UK
| | - Sophie L Russell
- Clinical Sciences and Translational Medicine Theme, Centre for Health and Life Sciences, Coventry University, Coventry, UK
| | - James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, ON, K1N 6N5, Canada
| | - Naoto Fujii
- Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
| | - Glen P Kenny
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, ON, K1N 6N5, Canada.
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7
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Gujarati NA, Frimpong BO, Zaidi M, Bronstein R, Revelo MP, Haley JD, Kravets I, Guo Y, Mallipattu SK. Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease. Nat Commun 2024; 15:8038. [PMID: 39271683 PMCID: PMC11399446 DOI: 10.1038/s41467-024-52306-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease worldwide. While injury to the podocytes, visceral epithelial cells that comprise the glomerular filtration barrier, drives albuminuria, proximal tubule (PT) dysfunction is the critical mediator of DKD progression. Here, we report that the podocyte-specific induction of human KLF6, a zinc-finger binding transcription factor, attenuates podocyte loss, PT dysfunction, and eventual interstitial fibrosis in a male murine model of DKD. Utilizing combination of snRNA-seq, snATAC-seq, and tandem mass spectrometry, we demonstrate that podocyte-specific KLF6 triggers the release of secretory ApoJ to activate calcium/calmodulin dependent protein kinase 1D (CaMK1D) signaling in neighboring PT cells. CaMK1D is enriched in the first segment of the PT, proximal to the podocytes, and is critical to attenuating mitochondrial fission and restoring mitochondrial function under diabetic conditions. Targeting podocyte-PT signaling by enhancing ApoJ-CaMK1D might be a key therapeutic strategy in attenuating the progression of DKD.
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Affiliation(s)
- Nehaben A Gujarati
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Bismark O Frimpong
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Malaika Zaidi
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Robert Bronstein
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Monica P Revelo
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - John D Haley
- Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA
| | - Igor Kravets
- Division of Endocrinology, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Yiqing Guo
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Sandeep K Mallipattu
- Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
- Renal Section, Northport VA Medical Center, Northport, NY, USA.
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8
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Polonsky M, Gerhardt LMS, Yun J, Koppitch K, Colón KL, Amrhein H, Wold B, Zheng S, Yuan GC, Thomson M, Cai L, McMahon AP. Spatial transcriptomics defines injury specific microenvironments and cellular interactions in kidney regeneration and disease. Nat Commun 2024; 15:7010. [PMID: 39237549 PMCID: PMC11377535 DOI: 10.1038/s41467-024-51186-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 08/01/2024] [Indexed: 09/07/2024] Open
Abstract
Kidney injury disrupts the intricate renal architecture and triggers limited regeneration, together with injury-invoked inflammation and fibrosis. Deciphering the molecular pathways and cellular interactions driving these processes is challenging due to the complex tissue structure. Here, we apply single cell spatial transcriptomics to examine ischemia-reperfusion injury in the mouse kidney. Spatial transcriptomics reveals injury-specific and spatially-dependent gene expression patterns in distinct cellular microenvironments within the kidney and predicts Clcf1-Crfl1 in a molecular interplay between persistently injured proximal tubule cells and their neighboring fibroblasts. Immune cell types play a critical role in organ repair. Spatial analysis identifies cellular microenvironments resembling early tertiary lymphoid structures and associated molecular pathways. Collectively, this study supports a focus on molecular interactions in cellular microenvironments to enhance understanding of injury, repair and disease.
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Affiliation(s)
- Michal Polonsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Louisa M S Gerhardt
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
- Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jina Yun
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kari Koppitch
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Katsuya Lex Colón
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Henry Amrhein
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Barbara Wold
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Shiwei Zheng
- Department of Genetics and Genomic Sciences and Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Guo-Cheng Yuan
- Department of Genetics and Genomic Sciences and Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matt Thomson
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Long Cai
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
| | - Andrew P McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
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9
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Pan W, Zhang W, Zheng B, Camellato BR, Stern J, Lin Z, Khodadadi-Jamayran A, Kim J, Sommer P, Khalil K, Weldon E, Bai J, Zhu Y, Meyn P, Heguy A, Mangiola M, Griesemer A, Keating BJ, Montgomery RA, Xia B, Boeke JD. Cellular dynamics in pig-to-human kidney xenotransplantation. MED 2024; 5:1016-1029.e4. [PMID: 38776915 DOI: 10.1016/j.medj.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/30/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Xenotransplantation of genetically engineered porcine organs has the potential to address the challenge of organ donor shortage. Two cases of porcine-to-human kidney xenotransplantation were performed, yet the physiological effects on the xenografts and the recipients' immune responses remain largely uncharacterized. METHODS We performed single-cell RNA sequencing (scRNA-seq) and longitudinal RNA-seq analyses of the porcine kidneys to dissect xenotransplantation-associated cellular dynamics and xenograft-recipient interactions. We additionally performed longitudinal scRNA-seq of the peripheral blood mononuclear cells (PBMCs) to detect recipient immune responses across time. FINDINGS Although no hyperacute rejection signals were detected, scRNA-seq analyses of the xenografts found evidence of endothelial cell and immune response activation, indicating early signs of antibody-mediated rejection. Tracing the cells' species origin, we found human immune cell infiltration in both xenografts. Human transcripts in the longitudinal bulk RNA-seq revealed that human immune cell infiltration and the activation of interferon-gamma-induced chemokine expression occurred by 12 and 48 h post-xenotransplantation, respectively. Concordantly, longitudinal scRNA-seq of PBMCs also revealed two phases of the recipients' immune responses at 12 and 48-53 h. Lastly, we observed global expression signatures of xenotransplantation-associated kidney tissue damage in the xenografts. Surprisingly, we detected a rapid increase of proliferative cells in both xenografts, indicating the activation of the porcine tissue repair program. CONCLUSIONS Longitudinal and single-cell transcriptomic analyses of porcine kidneys and the recipient's PBMCs revealed time-resolved cellular dynamics of xenograft-recipient interactions during xenotransplantation. These cues can be leveraged for designing gene edits and immunosuppression regimens to optimize xenotransplantation outcomes. FUNDING This work was supported by NIH RM1HG009491 and DP5OD033430.
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Affiliation(s)
- Wanqing Pan
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
| | - Weimin Zhang
- Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Binghan Zheng
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Brendan R Camellato
- Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Jeffrey Stern
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Ziyan Lin
- Applied Bioinformatics Laboratories (ABL), NYU Grossman School of Medicine, New York, NY 10016, USA
| | | | - Jacqueline Kim
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Philip Sommer
- Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Karen Khalil
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA
| | - Elaina Weldon
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Jiangshan Bai
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Yinan Zhu
- Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Peter Meyn
- Genome Technology Center, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Adriana Heguy
- Genome Technology Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Massimo Mangiola
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA
| | - Adam Griesemer
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Brendan J Keating
- Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Robert A Montgomery
- NYU Langone Transplant Institute, NYU Langone Health, New York, NY 10016, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA.
| | - Bo Xia
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA.
| | - Jef D Boeke
- Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
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10
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Beamish JA, Watts JA, Dressler GR. Gene regulation in regeneration after acute kidney injury. J Biol Chem 2024; 300:107520. [PMID: 38950862 PMCID: PMC11325799 DOI: 10.1016/j.jbc.2024.107520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024] Open
Abstract
Acute kidney injury (AKI) is a common condition associated with significant morbidity, mortality, and cost. Injured kidney tissue can regenerate after many forms of AKI. However, there are no treatments in routine clinical practice to encourage recovery. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that orchestrate kidney recovery. The advent of high-throughput sequencing technologies and genetic mouse models has opened an unprecedented window into the transcriptional dynamics that accompany both successful and maladaptive repair. AKI recovery shares similar cell-state transformations with kidney development, which can suggest common mechanisms of gene regulation. Several powerful bioinformatic strategies have been developed to infer the activity of gene regulatory networks by combining multiple forms of sequencing data at single-cell resolution. These studies highlight not only shared stress responses but also key changes in gene regulatory networks controlling metabolism. Furthermore, chromatin immunoprecipitation studies in injured kidneys have revealed dynamic epigenetic modifications at enhancer elements near target genes. This review will highlight how these studies have enhanced our understanding of gene regulation in injury response and regeneration.
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Affiliation(s)
- Jeffrey A Beamish
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jason A Watts
- Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Gregory R Dressler
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
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11
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Čugura T, Boštjančič E, Uhan S, Hauptman N, Jeruc J. Epithelial-mesenchymal transition associated markers in sarcomatoid transformation of clear cell renal cell carcinoma. Exp Mol Pathol 2024; 138:104909. [PMID: 38876079 DOI: 10.1016/j.yexmp.2024.104909] [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: 08/18/2023] [Revised: 05/18/2024] [Accepted: 06/03/2024] [Indexed: 06/16/2024]
Abstract
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development and progression of many cancers. Partial EMT (pEMT) could represent a critical step in tumor migration and dissemination. Sarcomatoid renal cell carcinoma (sRCC) is an aggressive form of renal cell carcinoma (RCC) composed of a carcinomatous (sRCC-Ca) and sarcomatous (sRCC-Sa) component. The role of (p)EMT in the progression of RCC to sRCC remains unclear. The aim of this study was to investigate the involvement of (p)EMT in RCC and sRCC. Tissue samples from 10 patients with clear cell RCC (ccRCC) and 10 patients with sRCC were selected. The expression of main EMT markers (miR-200 family, miR-205, SNAI1/2, TWIST1/2, ZEB1/2, CDH1/2, VIM) was analyzed by qPCR in ccRCC, sRCC-Ca, and sRCC-Sa and compared to non-neoplastic tissue and between both groups. Expression of E-cadherin, N-cadherin, vimentin and ZEB2 was analyzed using immunohistochemistry. miR-200c was downregulated in sRCC-Ca compared to ccRCC, while miR-200a was downregulated in sRCC-Sa compared to ccRCC. CDH1 was downregulated in sRCC-Sa when compared to any other group. ZEB2 was downregulated in ccRCC and sRCC compared to corresponding non-neoplastic kidney. A positive correlation was observed between CDH1 expression and miR-200a/b/c. Our results suggest that full EMT is not present in sRCC. Instead, discreet molecular differences exist between ccRCC, sRCC-Ca, and sRCC-Sa, possibly representing distinct intermediary states undergoing pEMT.
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MESH Headings
- Humans
- Epithelial-Mesenchymal Transition/genetics
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Kidney Neoplasms/pathology
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- MicroRNAs/genetics
- Male
- Middle Aged
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Female
- Vimentin/metabolism
- Vimentin/genetics
- Zinc Finger E-box Binding Homeobox 2/genetics
- Zinc Finger E-box Binding Homeobox 2/metabolism
- Aged
- Cadherins/genetics
- Cadherins/metabolism
- Gene Expression Regulation, Neoplastic
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Twist-Related Protein 1/genetics
- Twist-Related Protein 1/metabolism
- Snail Family Transcription Factors/genetics
- Snail Family Transcription Factors/metabolism
- Zinc Finger E-box-Binding Homeobox 1/genetics
- Zinc Finger E-box-Binding Homeobox 1/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Cell Transformation, Neoplastic/metabolism
- Adult
- Nuclear Proteins
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Affiliation(s)
- Tanja Čugura
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Sara Uhan
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Hauptman
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jera Jeruc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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12
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Pasten C, Lozano M, Osorio LA, Cisterna M, Jara V, Sepúlveda C, Ramírez-Balaguera D, Moreno-Hidalgo V, Arévalo-Gil D, Soto P, Hurtado V, Morales A, Méndez GP, Busso D, Leon P, Michea L, Corvalán D, Luarte A, Irarrazabal CE. The protective effect of 1400W against ischaemia and reperfusion injury is countered by transient medullary kidney endothelial dysregulation. J Physiol 2024. [PMID: 39057844 DOI: 10.1113/jp285944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 06/12/2024] [Indexed: 07/28/2024] Open
Abstract
Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition.
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Affiliation(s)
- Consuelo Pasten
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
- Facultad de Medicina, Universidad de los Andes, Chile
| | - Mauricio Lozano
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Luis A Osorio
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Matías Cisterna
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Valeria Jara
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Catalina Sepúlveda
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Daniela Ramírez-Balaguera
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Viviana Moreno-Hidalgo
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Dayana Arévalo-Gil
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Paola Soto
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Valeria Hurtado
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Antonia Morales
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | | | - Dolores Busso
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Biología de la Reproducción, Universidad de los Andes, Chile
| | - Pablo Leon
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Luis Michea
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Daniela Corvalán
- Neuroscience Program, Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Universidad de los Andes, Chile
| | - Alejandro Luarte
- Neuroscience Program, Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Universidad de los Andes, Chile
| | - Carlos E Irarrazabal
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
- Facultad de Medicina, Universidad de los Andes, Chile
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13
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Chen Y, Gong Y, Zou J, Li G, Zhang F, Yang Y, Liang Y, Dai W, He L, Lu H. Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation, fluid sheer stress, and inflammatory pathways in obesity-related glomerulopathy. Genes Dis 2024; 11:101101. [PMID: 38560497 PMCID: PMC10978546 DOI: 10.1016/j.gendis.2023.101101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 06/20/2023] [Accepted: 07/24/2023] [Indexed: 04/04/2024] Open
Abstract
Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.
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Affiliation(s)
- Yinyin Chen
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yushun Gong
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Jia Zou
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Guoli Li
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Fan Zhang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yiya Yang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yumei Liang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Wenni Dai
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
| | - Hengcheng Lu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
- Cardiovascular Research Institute of Jiangxi Province, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, China
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14
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Noonan ML, Muto Y, Yoshimura Y, Leckie-Harre A, Wu H, Kalinichenko VV, Humphreys BD, Chang-Panesso M. Injury-induced Foxm1 expression in the mouse kidney drives epithelial proliferation by a cyclin F-dependent mechanism. JCI Insight 2024; 9:e175416. [PMID: 38916959 PMCID: PMC11383596 DOI: 10.1172/jci.insight.175416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Acute kidney injury (AKI) strongly upregulates the transcription factor Foxm1 in the proximal tubule in vivo, and Foxm1 drives epithelial proliferation in vitro. Here, we report that deletion of Foxm1 either with a nephron-specific Cre driver or by inducible global deletion reduced proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI to chronic kidney disease transition, with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report ERK mediated FOXM1 induction downstream of the EGFR in primary proximal tubule cells. We defined FOXM1 genomic binding sites by cleavage under targets and release using nuclease (CUT&RUN) and compared the genes located near FOXM1 binding sites with genes downregulated in primary proximal tubule cells after FOXM1 knockdown. The aligned data sets revealed the cell cycle regulator cyclin F (CCNF) as a putative FOXM1 target. We identified 2 cis regulatory elements that bound FOXM1 and regulated CCNF expression, demonstrating that Ccnf is strongly induced after kidney injury and that Foxm1 deletion abrogates Ccnf expression in vivo and in vitro. Knockdown of CCNF also reduced proximal tubule proliferation in vitro. These studies identify an ERK/FOXM1/CCNF signaling pathway that regulates injury-induced proximal tubule cell proliferation.
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Affiliation(s)
- Megan L Noonan
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Yoshiharu Muto
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Yasuhiro Yoshimura
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Aidan Leckie-Harre
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Vladimir V Kalinichenko
- Phoenix Children's Health Research Institute, Department of Child Health, University of Arizona College of Medicine, Phoenix, Arizona, USA
- Division of Neonatology, Phoenix Children's Hospital, Phoenix, Arizona, USA
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
- Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Monica Chang-Panesso
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
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15
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Nerger BA, Sinha S, Lee NN, Cheriyan M, Bertsch P, Johnson CP, Mahadevan L, Bonventre JV, Mooney DJ. 3D Hydrogel Encapsulation Regulates Nephrogenesis in Kidney Organoids. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2308325. [PMID: 38180232 PMCID: PMC10994733 DOI: 10.1002/adma.202308325] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/06/2023] [Indexed: 01/06/2024]
Abstract
Stem cell-derived kidney organoids contain nephron segments that recapitulate morphological and functional aspects of the human kidney. However, directed differentiation protocols for kidney organoids are largely conducted using biochemical signals to control differentiation. Here, the hypothesis that mechanical signals regulate nephrogenesis is investigated in 3D culture by encapsulating kidney organoids within viscoelastic alginate hydrogels with varying rates of stress relaxation. Tubular nephron segments are significantly more convoluted in kidney organoids differentiated in encapsulating hydrogels when compared with those in suspension culture. Hydrogel viscoelasticity regulates the spatial distribution of nephron segments within the differentiating kidney organoids. Consistent with these observations, a particle-based computational model predicts that the extent of deformation of the hydrogel-organoid interface regulates the morphology of nephron segments. Elevated extracellular calcium levels in the culture medium, which can be impacted by the hydrogels, decrease the glomerulus-to-tubule ratio of nephron segments. These findings reveal that hydrogel encapsulation regulates nephron patterning and morphology and suggest that the mechanical microenvironment is an important design variable for kidney regenerative medicine.
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Affiliation(s)
- Bryan A. Nerger
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Sumit Sinha
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nathan N. Lee
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Maria Cheriyan
- Harvard College, Harvard University, Cambridge, MA 02138, USA
| | - Pascal Bertsch
- Radboud University Medical Center, Department of Dentistry – Regenerative Biomaterials, Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands
| | - Christopher P. Johnson
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - L. Mahadevan
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
| | - Joseph V. Bonventre
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - David J. Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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16
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Buse M, Cheng M, Jankowski V, Lellig M, Sterzer V, Strieder T, Leuchtle K, Martin IV, Seikrit C, Brinkkoettter P, Crispatzu G, Floege J, Boor P, Speer T, Kramann R, Ostendorf T, Moeller MJ, Costa IG, Stamellou E. Lineage tracing reveals transient phenotypic adaptation of tubular cells during acute kidney injury. iScience 2024; 27:109255. [PMID: 38444605 PMCID: PMC10914483 DOI: 10.1016/j.isci.2024.109255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 12/05/2023] [Accepted: 02/13/2024] [Indexed: 03/07/2024] Open
Abstract
Tubular injury is the hallmark of acute kidney injury (AKI) with a tremendous impact on patients and health-care systems. During injury, any differentiated proximal tubular cell (PT) may transition into a specific injured phenotype, so-called "scattered tubular cell" (STC)-phenotype. To understand the fate of this specific phenotype, we generated transgenic mice allowing inducible, reversible, and irreversible tagging of these cells in a murine AKI model, the unilateral ischemia-reperfusion injury (IRI). For lineage tracing, we analyzed the kidneys using single-cell profiling during disease development at various time points. Labeled cells, which we defined by established endogenous markers, already appeared 8 h after injury and showed a distinct expression set of genes. We show that STCs re-differentiate back into fully differentiated PTs upon the resolution of the injury. In summary, we show the dynamics of the phenotypic transition of PTs during injury, revealing a reversible transcriptional program as an adaptive response during disease.
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Affiliation(s)
- Marc Buse
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Mingbo Cheng
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
| | - Vera Jankowski
- Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany
| | - Michaela Lellig
- Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany
| | - Viktor Sterzer
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Thiago Strieder
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Katja Leuchtle
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Ina V. Martin
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Claudia Seikrit
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Paul Brinkkoettter
- Department II of Internal Medicine and Centre for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Giuliano Crispatzu
- Department II of Internal Medicine and Centre for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Peter Boor
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Timotheus Speer
- Medical Clinic 4, Nephrology, University of Frankfurt und Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Tammo Ostendorf
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Marcus J. Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Ivan G. Costa
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
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17
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Zhou R, Liu H, Hou X, Liu Q, Sun S, Li X, Cao W, Nie W, Shi C, Chen W. Bi-functional KIT-PR1P peptides combine with VEGF to protect ischemic kidney in rats by targeting to Kim-1. Regen Ther 2024; 25:162-173. [PMID: 38178930 PMCID: PMC10765240 DOI: 10.1016/j.reth.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 01/06/2024] Open
Abstract
Introduction Acute kidney injury (AKI) was a disease with a high mortality mainly caused by renal ischemia/reperfusion injury (I/R). Although the current non-targeted administration of vascular endothelial growth factor (VEGF) for AKI had been revealed to facilitate the recovery of renal I/R, how to targeted deliver VEGF and to retain it efficiently in the ischemic kidney was critical for its clinical application. Methods In present study, bi-functional KIT-PR1P peptides were constructed which bond VEGF through PR1P domain, and targeted ischemic kidney through KIT domain to interact with biomarker of AKI-kidney injury molecule-1 (Kim-1). Then the targeted and therapeutic effects of KIT-PR1P/VEGF in AKI was explored in vitro and in vivo. Results The results showed KIT-PR1P exhibited better angiogenic capacity and targeting ability to hypoxia HK-2 cells with up-regulated Kim-1 in vitro. When KIT-PR1P/VEGF was used for the treatment of renal I/R through intravenous administration in vivo, KIT-PR1P could guide VEGF and retain its effective concentration in ischemic kidney. In addition, KIT-PR1P/VEGF promoted angiogenesis, alleviated renal tubular injury and fibrosis, and finally promoted functional recovery of renal I/R. Conclusion These results indicated that the bi-functional KIT-PR1P peptides combined with VEGF would be a promising strategy for the treatment of AKI by targeting to Kim-1.
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Affiliation(s)
- Runxue Zhou
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Hang Liu
- Department of Nephropathy, The Affiliated Hospital of Qingdao University, Qingdao, 266700, China
| | - Xianglin Hou
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics Cand Developmental Biology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Qi Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Department of Neurology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, 266000, China
| | - Shuwei Sun
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaoge Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wenxuan Cao
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Weihong Nie
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Chunying Shi
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wei Chen
- Department of Urology, Xinqiao Hospital, Army Medical University, Chongqing, 400038, China
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18
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Bahrami M, Darabi S, Roozbahany NA, Abbaszadeh HA, Moghadasali R. Great potential of renal progenitor cells in kidney: From the development to clinic. Exp Cell Res 2024; 434:113875. [PMID: 38092345 DOI: 10.1016/j.yexcr.2023.113875] [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: 11/08/2023] [Revised: 12/02/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Abstract
The mammalian renal organ represents a pinnacle of complexity, housing functional filtering units known as nephrons. During embryogenesis, the depletion of niches containing renal progenitor cells (RPCs) and the subsequent incapacity of adult kidneys to generate new nephrons have prompted the formulation of protocols aimed at isolating residual RPCs from mature kidneys and inducing their generation from diverse cell sources, notably pluripotent stem cells. Recent strides in the realm of regenerative medicine and the repair of tissues using stem cells have unveiled critical signaling pathways essential for the maintenance and generation of human RPCs in vitro. These findings have ushered in a new era for exploring novel strategies for renal protection. The present investigation delves into potential transcription factors and signaling cascades implicated in the realm of renal progenitor cells, focusing on their protection and differentiation. The discourse herein elucidates contemporary research endeavors dedicated to the acquisition of progenitor cells, offering crucial insights into the developmental mechanisms of these cells within the renal milieu and paving the way for the formulation of innovative treatment modalities.
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Affiliation(s)
- Maryam Bahrami
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Applications in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Hojjat Allah Abbaszadeh
- Laser Applications in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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19
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Nourie N, Ghaleb R, Lefaucheur C, Louis K. Toward Precision Medicine: Exploring the Landscape of Biomarkers in Acute Kidney Injury. Biomolecules 2024; 14:82. [PMID: 38254682 PMCID: PMC10813773 DOI: 10.3390/biom14010082] [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: 12/16/2023] [Revised: 01/02/2024] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Acute kidney injury (AKI) remains a complex challenge with diverse underlying pathological mechanisms and etiologies. Current detection methods predominantly rely on serum creatinine, which exhibits substantial limitations in specificity and poses the issue of late-stage detection of kidney injury. In this review, we propose an up-to-date and comprehensive summary of advancements that identified novel biomarker candidates in blood and urine and ideal criteria for AKI biomarkers such as renal injury specificity, mechanistic insight, prognostic capacity, and affordability. Recently identified biomarkers not only indicate injury location but also offer valuable insights into a range of pathological processes, encompassing reduced glomerular filtration rate, tubular function, inflammation, and adaptive response to injury. The clinical applications of AKI biomarkers are becoming extensive and serving as relevant tools in distinguishing acute tubular necrosis from other acute renal conditions. Also, these biomarkers can offer significant insights into the risk of progression to chronic kidney disease CKD and in the context of kidney transplantation. Integration of these biomarkers into clinical practice has the potential to improve early diagnosis of AKI and revolutionize the design of clinical trials, offering valuable endpoints for therapeutic interventions and enhancing patient care and outcomes.
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Affiliation(s)
- Nicole Nourie
- Department of Nephrology and Kidney Transplantation, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, 75010 Paris, France
- Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, 75010 Paris, France
| | - Rita Ghaleb
- Faculty of Medicine, Saint Joseph University, Beirut 1104 2020, Lebanon
| | - Carmen Lefaucheur
- Department of Nephrology and Kidney Transplantation, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, 75010 Paris, France
- Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, 75010 Paris, France
| | - Kevin Louis
- Department of Nephrology and Kidney Transplantation, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, 75010 Paris, France
- Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, 75010 Paris, France
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20
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Matouk AI, Awad EM, Mousa AAK, Abdelhafez SMN, Fahmy UA, El-Moselhy MA, Abdel-Naim AB, Anter A. Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2. Life Sci 2024; 336:122318. [PMID: 38035992 DOI: 10.1016/j.lfs.2023.122318] [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: 08/24/2023] [Revised: 11/06/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
AIM Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.
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Affiliation(s)
- Asmaa I Matouk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt.
| | - Eman M Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Amr A K Mousa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Sara M N Abdelhafez
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Usama A Fahmy
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohamed A El-Moselhy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt; Clinical Pharmacy and Pharmacology Department, Ibn Sina National College for Medical Studies, Jeddah 21589, Saudi Arabia
| | - Ashraf B Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aliaa Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
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21
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Chui H, McMahon KR, Rassekh SR, Schultz KR, Blydt-Hansen TD, Mammen C, Pinsk M, Cuvelier GDE, Carleton BC, Tsuyuki RT, Ross CJD, Devarajan P, Huynh L, Yordanova M, Crépeau-Hubert F, Wang S, Cockovski V, Palijan A, Zappitelli M. Urinary TIMP-2*IGFBP-7 to diagnose acute kidney injury in children receiving cisplatin. Pediatr Nephrol 2024; 39:269-282. [PMID: 37365422 DOI: 10.1007/s00467-023-06007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers. METHODS We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). PRIMARY OUTCOME serum creatinine (SCr)-defined AKI (≥ stage 1). RESULTS At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine)2/1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70). CONCLUSIONS TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Hayton Chui
- Department of Pediatrics, Division of Nephrology, Peter Gilgan Centre For Research and Learning, Child Health Evaluative Sciences, Toronto Hospital for Sick Children, University of Toronto, Room 11th Floor, 11.9722, 686 Bay Street, Toronto, ON, M5G 0A4, Canada
- Faculty of Health Sciences, Queen's University, Kingston, ON, Canada
| | - Kelly R McMahon
- Department of Pediatrics, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Shahrad Rod Rassekh
- Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Kirk R Schultz
- Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, Division of Pediatric Nephrology, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Cherry Mammen
- Department of Pediatrics, Division of Pediatric Nephrology, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Maury Pinsk
- Department of Pediatrics and Child Health, Section of Pediatric Nephrology, University of Manitoba, Winnipeg, MB, Canada
| | - Geoffrey D E Cuvelier
- Department of Pediatrics and Child Health, Division of Pediatric Oncology-Hematology-BMT, University of Manitoba, CancerCare Manitoba, Winnipeg, MB, Canada
| | - Bruce C Carleton
- Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia and BC Children's Hospital and Research Institute, Vancouver, BC, Canada
| | - Ross T Tsuyuki
- Epidemiology Coordinating and Research (EPICORE) Centre, Departments of Medicine and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Colin J D Ross
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Prasad Devarajan
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Louis Huynh
- Faculty of Health Sciences, Queen's University, Kingston, ON, Canada
| | - Mariya Yordanova
- Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Frédérik Crépeau-Hubert
- Department of Pediatrics, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Stella Wang
- Department of Pediatrics, Division of Nephrology, Peter Gilgan Centre For Research and Learning, Child Health Evaluative Sciences, Toronto Hospital for Sick Children, University of Toronto, Room 11th Floor, 11.9722, 686 Bay Street, Toronto, ON, M5G 0A4, Canada
| | - Vedran Cockovski
- Department of Pediatrics, Division of Nephrology, Peter Gilgan Centre For Research and Learning, Child Health Evaluative Sciences, Toronto Hospital for Sick Children, University of Toronto, Room 11th Floor, 11.9722, 686 Bay Street, Toronto, ON, M5G 0A4, Canada
| | - Ana Palijan
- Department of Pediatrics, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Michael Zappitelli
- Department of Pediatrics, Division of Nephrology, Peter Gilgan Centre For Research and Learning, Child Health Evaluative Sciences, Toronto Hospital for Sick Children, University of Toronto, Room 11th Floor, 11.9722, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
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22
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Convento MB, de Oliveira AS, Boim MA, Borges FT. Mesenchymal Stromal Cells Nanovesicles Carry microRNA with Nephroprotective Proprieties Regardless of Aging. Curr Aging Sci 2024; 17:118-126. [PMID: 38904154 DOI: 10.2174/0118746098272926231107061047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/27/2023] [Accepted: 09/15/2023] [Indexed: 06/22/2024]
Abstract
Containing information molecules from their parent cells and inclining to fuse with targeted cells, bone marrow mesenchymal stromal cells-derived extracellular vesicles (MSCs- EV) are valuable in nanomedicine. BACKGROUND The effects of aging on the paracrine mechanism and in the production and action of MSCs-EV and their cargos of miR-26a and siRNA-26a for the treatment of tubular renal cells under nephrotoxicity injury remain unelucidated. OBJECTIVE The purpose of this study was to evaluate MSCs-EV of different ages and their ability to deliver the cargos of miR-26a and siRNA-26a to target renal tubular cells affected by nephrotoxicity injury. METHODS In a model of gentamicin-induced nephrotoxicity, renal tubular cells treated with MSCs-EV expressing or not expressing microRNA-26a were analyzed. Western blotting was utilized to evaluate cell cycle markers, and MTT assay was utilized to evaluate auto-renovation capacity. RESULTS Tubular cells under nephrotoxicity injury showed decreased proliferative capacity, but the treatment in the tubular renal cells under nephrotoxicity injury with MSCs-EV expressing microRNA-26a showed nephroprotective effects, regardless of EV age. While the treatment with EV-mediated siRNA-26a failed to preserve the nephroprotective effects equally, regardless of age. CONCLUSION Mesenchymal stromal cell nanovesicles carry microRNA with nephroprotective proprieties regardless of aging.
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Affiliation(s)
- Marcia Bastos Convento
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Street Borges Lagoa, 783, 6º Floor, Doctors' Building, Sao Paulo - SP - CEP 04038-901, Brazil
| | - Andréia Silva de Oliveira
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Street Borges Lagoa, 783, 6º Floor, Doctors' Building, Sao Paulo - SP - CEP 04038-901, Brazil
| | - Mirian Aparecida Boim
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Street Borges Lagoa, 783, 6º Floor, Doctors' Building, Sao Paulo - SP - CEP 04038-901, Brazil
| | - Fernanda Teixeira Borges
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Street Borges Lagoa, 783, 6º Floor, Doctors' Building, Sao Paulo - SP - CEP 04038-901, Brazil
- Interdisciplinary Postgraduate Program in Health Sciences, Cruzeiro do Sul University, Street Galvão Bueno, 868 - Sao Paulo - SP, 01506-000, Brazil
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23
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Rossiter A, La A, Koyner JL, Forni LG. New biomarkers in acute kidney injury. Crit Rev Clin Lab Sci 2024; 61:23-44. [PMID: 37668397 DOI: 10.1080/10408363.2023.2242481] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/14/2023] [Accepted: 07/26/2023] [Indexed: 09/06/2023]
Abstract
Acute kidney injury (AKI) is a commonly encountered clinical syndrome. Although it often complicates community acquired illness, it is more common in hospitalized patients, particularly those who are critically ill or who have undergone major surgery. Approximately 20% of hospitalized adult patients develop an AKI during their hospital care, and this rises to nearly 60% in the critically ill, depending on the population being considered. In general, AKI is more common in older adults, in those with preexisting chronic kidney disease and in those with known risk factors for AKI (including diabetes and hypertension). The development of AKI is associated with an increase in both mortality and morbidity, including the development of post-AKI chronic kidney disease. Currently, AKI is defined by a rise in serum creatinine from either a known or derived baseline value and/or oliguria or anuria. However, clinicians may fail to recognize the initial development of AKI because of a delay in the rise of serum creatinine or because of inaccurate urine output monitoring. This, in turn, delays any putative measures to treat AKI or to limit its degree. Consequently, efforts have focused on new biomarkers associated with AKI that may allow early recognition of this syndrome with the intent that this will translate into improved patient outcomes. Here we outline current biomarkers associated with AKI and explore their potential in aiding diagnosis, understanding the pathophysiology and directing therapy.
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Affiliation(s)
- Adam Rossiter
- Critical Care Unit, Royal Surrey Hospital, Guildford, Surry, UK
| | - Ashley La
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Jay L Koyner
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Lui G Forni
- Critical Care Unit, Royal Surrey Hospital, Guildford, Surry, UK
- School of Medicine, Department of Clinical & Experimental Medicine, Faculty of Health Sciences, University of Surrey, Surry, UK
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24
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Le Sueur ANV, de Souza AAL, Paes AC, Takahira RK, Melchert A, Okamoto AS, Coyne M, Murphy R, Szlosek D, Peterson S, Guimarães-Okamoto PTC. Novel renal injury markers in dogs with ehrlichiosis. PLoS One 2023; 18:e0293545. [PMID: 38096157 PMCID: PMC10721078 DOI: 10.1371/journal.pone.0293545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/13/2023] [Indexed: 12/17/2023] Open
Abstract
Canine monocytic ehrlichiosis (CME) has been observed to impact renal function. Currently, the recognition of acute kidney injury is through the nonspecific biomarker serum creatinine (sCr). Novel markers of renal injury such as urinary clusterin (uClust) and urinary cystatin B (uCysB) may increase our understanding of the relationship between ehrlichiosis and renal cellular injury. The aim of this study was to evaluate novel renal injury biomarkers in dogs with acute CME. Twenty healthy dogs were enrolled in the control group (CG), and 16 dogs naturally infected with Ehrlichia canis were included in the Ehrlichia Group (EG). All dogs were followed for 45 days. EG dogs were treated with doxycycline twice daily for the first 30 days. Urine and serum were collected at: 0, 0.5, 1, 15, 30, and 45 days after start of treatment. Urine concentrations of uClust and uCysB were determined using a research ELISA immunoassay. A linear mixed model was used to estimate population mean of renal injury markers with patient as the random effect, and day and treatment as fixed effects. EG was observed to have higher uClust values compared to CG (estimated population mean EG: 213 ng/dL vs. CG: 84 ng/dL, P < 0.001). EG was observed to have higher uCysB values compared to CG (estimated population mean EG: 248 ng/dL vs. CG: 38 ng/dL, P < 0.001). Increases in uCysB and uClust suggest the presence of renal injury and a possible mechanism for the observed predisposition to chronic kidney disease in dogs with ehrlichiosis.
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Affiliation(s)
- André N. V. Le Sueur
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University - NCSU, Raleigh, North Carolina, United States of America
| | - Adriana A. L. de Souza
- Department of Animal Production and Preventive Veterinary Medicine, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
| | - Antônio C. Paes
- Department of Animal Production and Preventive Veterinary Medicine, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
| | - Regina K. Takahira
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
| | - Alessandra Melchert
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
| | - Adriano S. Okamoto
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
| | - Michael Coyne
- IDEXX Laboratories Inc., Westbrook, Maine, United States of America
| | - Rachel Murphy
- Abbott Diagnostics Inc., Scarborough, Maine, United States of America
| | - Donald Szlosek
- IDEXX Laboratories Inc., Westbrook, Maine, United States of America
| | - Sarah Peterson
- IDEXX Laboratories Inc., Westbrook, Maine, United States of America
| | - Priscylla T. C. Guimarães-Okamoto
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University - UNESP, Botucatu, Brazil
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25
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Polonsky M, Gerhardt LMS, Yun J, Koppitch K, Colón KL, Amrhein H, Zheng S, Yuan GC, Thomson M, Cai L, McMahon AP. Spatial transcriptomics defines injury-specific microenvironments in the adult mouse kidney and novel cellular interactions in regeneration and disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.22.568217. [PMID: 38045285 PMCID: PMC10690238 DOI: 10.1101/2023.11.22.568217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Kidney injury disrupts the intricate renal architecture and triggers limited regeneration, and injury-invoked inflammation and fibrosis. Deciphering molecular pathways and cellular interactions driving these processes is challenging due to the complex renal architecture. Here, we applied single cell spatial transcriptomics to examine ischemia-reperfusion injury in the mouse kidney. Spatial transcriptomics revealed injury-specific and spatially-dependent gene expression patterns in distinct cellular microenvironments within the kidney and predicted Clcf1-Crfl1 in a molecular interplay between persistently injured proximal tubule cells and neighboring fibroblasts. Immune cell types play a critical role in organ repair. Spatial analysis revealed cellular microenvironments resembling early tertiary lymphoid structures and identified associated molecular pathways. Collectively, this study supports a focus on molecular interactions in cellular microenvironments to enhance understanding of injury, repair and disease.
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Affiliation(s)
- Michal Polonsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Louisa M. S. Gerhardt
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Jina Yun
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kari Koppitch
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Katsuya Lex Colón
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Henry Amrhein
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Shiwei Zheng
- Department of Genetics and Genomic Sciences and Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Guo-Cheng Yuan
- Department of Genetics and Genomic Sciences and Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matt Thomson
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Long Cai
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Andrew P. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
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26
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Copur S, Yavuz F, Covic A, Kanbay M. A review on renal autologous cell transplantation: an investigational approach towards chronic kidney disease. Int Urol Nephrol 2023; 55:2539-2544. [PMID: 36971874 DOI: 10.1007/s11255-023-03574-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
Chronic kidney disease is among the most common causes of mortality and morbidity in adult population with limited therapeutic approaches including various medications and kidney replacement therapies. Kidney transplantation is the gold standard therapeutic alternative for the management of chronic kidney disease; nonetheless, important drawbacks include the lack of adequate living or deceased donors, high rates of pre- and post-operative complications including surgical complications, infectious complications and medication-induced adverse effects. With the latest preclinical and in vitro studies demonstrating the potentiality of kidney cells obtained from diseased kidneys to convert into fully functional kidney cells lead to a novel therapeutic alternative referred as autologous selected renal cell transplantation. Even though the clinical studies investigating the efficiency and adverse effects of autologous selected renal cell transplantation are limited, it is no doubt promising. The need for future large-scale studies on chronic kidney disease patients from a diversity of etiologies is clear for the better establishment of the therapeutic potential of autologous selected renal cell transplantation. In this narrative review, our aim is to evaluate the role of renal autologous stem cell therapy in the management of chronic kidney disease.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, 34010, Istanbul, Turkey
| | - Furkan Yavuz
- Department of Medicine, Koc University School of Medicine, 34010, Istanbul, Turkey
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa University of Medicine, Iasi, Romania
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.
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27
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Bordoni L, Kristensen AM, Sardella D, Kidmose H, Pohl L, Krag SRP, Schiessl IM. Longitudinal tracking of acute kidney injury reveals injury propagation along the nephron. Nat Commun 2023; 14:4407. [PMID: 37479698 PMCID: PMC10362041 DOI: 10.1038/s41467-023-40037-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 07/10/2023] [Indexed: 07/23/2023] Open
Abstract
Acute kidney injury (AKI) is an important risk factor for chronic kidney disease (CKD), but the underlying mechanisms of failed tubule repair and AKI-CKD transition are incompletely understood. In this study, we aimed for dynamic tracking of tubule injury and remodeling to understand if focal injury upon AKI may spread over time. Here, we present a model of AKI, in which we rendered only half of the kidney ischemic. Using serial intravital 2-photon microscopy and genetic identification of cycling cells, we tracked dynamic tissue remodeling in post- and non-ischemic kidney regions simultaneously and over 3 weeks. Spatial and temporal analysis of cycling cells relative to initial necrotic cell death demonstrated pronounced injury propagation and expansion into non-necrotic tissue regions, which predicted tubule atrophy with epithelial VCAM1 expression. In summary, our longitudinal analyses of tubule injury, remodeling, and fate provide important insights into AKI pathology.
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Affiliation(s)
- Luca Bordoni
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- GliaLab and Letten Centre, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | | | - Donato Sardella
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Hanne Kidmose
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Layla Pohl
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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28
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Erichsen L, Thimm C, Wruck W, Kaierle D, Schless M, Huthmann L, Dimski T, Kindgen-Milles D, Brandenburger T, Adjaye J. Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model. Int J Mol Sci 2023; 24:ijms24098228. [PMID: 37175937 PMCID: PMC10179415 DOI: 10.3390/ijms24098228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10-15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest.
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Affiliation(s)
- Lars Erichsen
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Wasco Wruck
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Daniela Kaierle
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Manon Schless
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Laura Huthmann
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Thomas Dimski
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Detlef Kindgen-Milles
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Timo Brandenburger
- Department of Anesthesiology, University Hospital Düsseldorf, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
- Zayed Centre for Research into Rare Diseases in Children (ZCR), EGA Institute for Women's Health, University College London (UCL), 20 Guilford Street, London WC1N 1DZ, UK
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29
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Gerhardt LM, Koppitch K, van Gestel J, Guo J, Cho S, Wu H, Kirita Y, Humphreys BD, McMahon AP. Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury. J Am Soc Nephrol 2023; 34:554-571. [PMID: 36735940 PMCID: PMC10103206 DOI: 10.1681/asn.0000000000000057] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/17/2022] [Indexed: 01/22/2023] Open
Abstract
SIGNIFICANCE STATEMENT Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI and their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells and single-nucleus multiomics (profiling transcriptome and chromatin accessibility) after AKI. They demonstrated that AKI triggers a cell-cycle response in most epithelial and nonepithelial kidney cell types. They also showed that maladaptive proinflammatory proximal tubule cells (PTCs) persist until 6 months post-AKI, although they decreased in abundance over time, in part, through cell death. Single-nucleus multiomics of lineage-traced cells revealed regulatory features of adaptive and maladaptive repair. These included activation of cell state-specific transcription factors and cis-regulatory elements, and effects in PTCs even after adaptive repair, weeks after the injury event. BACKGROUND AKI triggers a proliferative response as part of an intrinsic cellular repair program, which can lead to adaptive renal repair, restoring kidney structure and function, or maladaptive repair with the persistence of injured proximal tubule cells (PTCs) and an altered kidney structure. However, the cellular and molecular understanding of these repair programs is limited. METHODS To examine chromatin and transcriptional responses in the same cell upon ischemia-reperfusion injury (IRI), we combined genetic fate mapping of cycling ( Ki67+ ) cells labeled early after IRI with single-nucleus multiomics-profiling transcriptome and chromatin accessibility in the same nucleus-and generated a dataset of 83,315 nuclei. RESULTS AKI triggered a broad cell cycle response preceded by cell type-specific and global transcriptional changes in the nephron, the collecting and vascular systems, and stromal and immune cell types. We observed a heterogeneous population of maladaptive PTCs throughout proximal tubule segments 6 months post-AKI, with a marked loss of maladaptive cells from 4 weeks to 6 months. Gene expression and chromatin accessibility profiling in the same nuclei highlighted differences between adaptive and maladaptive PTCs in the activity of cis-regulatory elements and transcription factors, accompanied by corresponding changes in target gene expression. Adaptive repair was associated with reduced expression of genes encoding transmembrane transport proteins essential to kidney function. CONCLUSIONS Analysis of genome organization and gene activity with single-cell resolution using lineage tracing and single-nucleus multiomics offers new insight into the regulation of renal injury repair. Weeks to months after mild-to-moderate IRI, maladaptive PTCs persist with an aberrant epigenetic landscape, and PTCs exhibit an altered transcriptional profile even following adaptive repair.
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Affiliation(s)
- Louisa M.S. Gerhardt
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Kari Koppitch
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Jordi van Gestel
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California
- Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Jinjin Guo
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Sam Cho
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Yuhei Kirita
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Benjamin D. Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Department of Developmental Biology, Washington University in St. Louis, St. Louis, Missouri
| | - Andrew P. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
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30
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El-Daly SM, El-Bana MA, Abd El-Rahman SS, Latif YA, Medhat D. Dynamic expression of H19 and MALAT1 and their correlation with tumor progression biomarkers in a multistage hepatocarcinogenesis model. Cell Biochem Funct 2023; 41:331-343. [PMID: 36861261 DOI: 10.1002/cbf.3785] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/29/2022] [Accepted: 02/14/2023] [Indexed: 03/03/2023]
Abstract
Hepatocellular carcinoma (HCC) progresses sequentially in a stepwise pattern. Long noncoding RNA (lncRNA) can regulate the complex cascade of hepatocarcinogenesis. Our study aimed to elucidate the expression profile of H19 and MALAT1 during the different stages of hepatocarcinogenesis and the correlation between H19 and MALAT1 with the genes implicated in the carcinogenesis cascade. We employed a chemically induced hepatocarcinogenesis murine model to mimic the successive stages of human HCC development. Using real-time PCR, we analyzed the expression patterns of H19 and MALAT1, as well as the expression of biomarkers implicated in the Epithelial-Mesenchymal transition (EMT). The protein expression of the mesenchymal marker vimentin was also evaluated using immunohistochemistry in the stepwise induced stages. The histopathological evaluation of the liver tissue sections revealed significant changes during the experiment, with HCC developing at the final stage. Throughout the stages, there was a dynamic significant increase in the expression of H19 and MALAT1 compared to the normal control. Nevertheless, there was no significant difference between each stage and the preceding one. The tumor progression biomarkers (Matrix Metalloproteinases, vimentin, and β-catenin) exhibited the same trend of steadily increasing levels. However, in the case of Zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2), the significant elevation was only detected at the last stage of induction. The correlation between lncRNAs and the tumor progression biomarkers revealed a strong positive correlation between the expression pattern of H19 and MALAT1 with Matrix Metalloproteinases 2 and 9 and vimentin. Our findings imply that genetic and epigenetic alterations influence HCC development in a stepwise progressive pattern.
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Affiliation(s)
- Sherien M El-Daly
- Medical Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt.,Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt
| | - Mona A El-Bana
- Medical Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt
| | - Sahar S Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Yasmin Abdel Latif
- Medical Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt.,Faculty of Biotechnology, October University for Modern Sciences and Arts, 6th October, Giza, Egypt
| | - Dalia Medhat
- Medical Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt
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31
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Chivers JM, Whiles SA, Miles CB, Biederman BE, Ellison MF, Lovingood CW, Wright MH, Hoover DB, Raafey MA, Youngberg GA, Venkatachalam MA, Zheleznova NN, Yang C, Liu P, Kriegel AJ, Cowley AW, O'Connor PM, Picken MM, Polichnowski AJ. Brown-Norway chromosome 1 mitigates the upregulation of proinflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi rats. Am J Physiol Renal Physiol 2023; 324:F193-F210. [PMID: 36475869 PMCID: PMC9886360 DOI: 10.1152/ajprenal.00145.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 12/13/2022] Open
Abstract
Chronic kidney disease (CKD) has a strong genetic component; however, the underlying pathways are not well understood. Dahl salt-sensitive (SS)/Jr rats spontaneously develop CKD with age and are used to investigate the genetic determinants of CKD. However, there are currently several genetically diverse Dahl SS rats maintained at various institutions and the extent to which some exhibit age-related CKD is unclear. We assessed glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) in 3- and 6-mo-old male and female SS/JrHsdMcwi, BN/NHsd/Mcwi [Brown-Norway (BN)], and consomic SS-Chr 1BN/Mcwi (SS.BN1) rats, in which chromosome 1 from the BN rat was introgressed into the genome of the SS/JrHsdMcwi rat. Rats were fed a 0.4% NaCl diet. GS (31 ± 3% vs. 7 ± 1%) and TIF (2.3 ± 0.2 vs. 0.5 ± 0.1) were significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi rats, and CKD was exacerbated in males. GS was minimal in 6- and 3-mo-old BN (3.9 ± 0.6% vs. 1.2 ± 0.4%) and SS.BN1 (2.4 ± 0.5% vs. 1.0 ± 0.3%) rats, and neither exhibited TIF. In SS/JrHsdMcwi and SS.BN1 rats, mean arterial blood pressure was significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi (162 ± 4 vs. 131 ± 2 mmHg) but not SS.BN1 (115 ± 2 vs. 116 ± 1 mmHg) rats. In 6-mo-old SS/JrHsdMcwi rats, blood pressure was significantly greater in females. RNA-sequencing analysis revealed that inflammatory pathways were upregulated in isolated medullary thick ascending tubules in 7-wk-old SS/JrHsdMcwi rats, before the development of tubule pathology, compared with SS.BN1 rats. In summary, SS/JrHsdMcwi rats exhibit robust age-related progression of medullary thick ascending limb abnormalities, CKD, and hypertension, and gene(s) on chromosome 1 have a major pathogenic role in such changes.NEW & NOTEWORTHY This study shows that the robust age-related progression of kidney disease in Dahl SS/JrHsdMcw rats maintained on a normal-salt diet is abolished in consomic SS.BN1 rats. Evidence that medullary thick ascending limb segments of SS/JrHsdMcw rats are structurally abnormal and enriched in proinflammatory pathways before the development of protein casts provides new insights into the pathogenesis of kidney disease in this model.
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Affiliation(s)
- Jacqueline M Chivers
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Shannon A Whiles
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Conor B Miles
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Brianna E Biederman
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Megan F Ellison
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Connor W Lovingood
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Marie H Wright
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
| | - Donald B Hoover
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
- Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee
| | - Muhammad A Raafey
- Department of Pathology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee
| | - George A Youngberg
- Department of Pathology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee
| | | | | | - Chun Yang
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Pengyuan Liu
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Alison J Kriegel
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Allen W Cowley
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Paul M O'Connor
- Department of Physiology, Augusta University, Augusta, Georgia
| | - Maria M Picken
- Department of Pathology, Loyola University Medical Center, Maywood, Illinois
| | - Aaron J Polichnowski
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee
- Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee
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32
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Eymael J, van den Broek M, Miesen L, Monge VV, van den Berge BT, Mooren F, Velez VL, Dijkstra J, Hermsen M, Bándi P, Vermeulen M, de Wildt S, Willemsen B, Florquin S, Wetzels R, Steenbergen E, Kramann R, Moeller M, Schreuder MF, Wetzels JF, van der Vlag J, Jansen J, Smeets B. Human scattered tubular cells represent a heterogeneous population of glycolytic dedifferentiated proximal tubule cells. J Pathol 2023; 259:149-162. [PMID: 36373978 PMCID: PMC10107692 DOI: 10.1002/path.6029] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/22/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022]
Abstract
Scattered tubular cells (STCs) are a phenotypically distinct cell population in the proximal tubule that increase in number after acute kidney injury. We aimed to characterize the human STC population. Three-dimensional human tissue analysis revealed that STCs are preferentially located within inner bends of the tubule and are barely present in young kidney tissue (<2 years), and their number increases with age. Increased STC numbers were associated with acute tubular injury (kidney injury molecule 1) and interstitial fibrosis (alpha smooth muscle actin). Isolated CD13+ CD24- CD133- proximal tubule epithelial cells (PTECs) and CD13+ CD24+ and CD13+ CD133+ STCs were analyzed using RNA sequencing. Transcriptome analysis revealed an upregulation of nuclear factor κB, tumor necrosis factor alpha, and inflammatory pathways in STCs, whereas metabolism, especially the tricarboxylic acid cycle and oxidative phosphorylation, was downregulated, without showing signs of cellular senescence. Using immunostaining and a publicly available single-cell sequencing database of human kidneys, we demonstrate that STCs represent a heterogeneous population in a transient state. In conclusion, STCs are dedifferentiated PTECs showing a metabolic shift toward glycolysis, which could facilitate cellular survival after kidney injury. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jennifer Eymael
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn van den Broek
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Laura Miesen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Valerie Villacorta Monge
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bartholomeus T van den Berge
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fieke Mooren
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Vicky Luna Velez
- Department of Molecular Biology, Radboud Institute for Molecular Life Science, Nijmegen, The Netherlands
| | - Jelmer Dijkstra
- Department of Molecular Biology, Radboud Institute for Molecular Life Science, Nijmegen, The Netherlands
| | - Meyke Hermsen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Péter Bándi
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Radboud Institute for Molecular Life Science, Nijmegen, The Netherlands
| | - Saskia de Wildt
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Science, Nijmegen, The Netherlands
| | - Brigith Willemsen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sandrine Florquin
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Institute for Infection and Immunology, Amsterdam, The Netherlands
| | - Roy Wetzels
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eric Steenbergen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.,Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marcus Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Jack Fm Wetzels
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jitske Jansen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Bart Smeets
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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33
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Ciarambino T, Crispino P, Giordano M. Gender and Renal Insufficiency: Opportunities for Their Therapeutic Management? Cells 2022; 11:cells11233820. [PMID: 36497080 PMCID: PMC9740491 DOI: 10.3390/cells11233820] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 11/30/2022] Open
Abstract
Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies.
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Affiliation(s)
- Tiziana Ciarambino
- Internal Medicine Department, Hospital of Marcianise, ASL Caserta, 81031 Caserta, Italy
- Correspondence: (T.C.); (M.G.)
| | - Pietro Crispino
- Emergency Department, Hospital of Latina, ASL Latina, 04100 Latina, Italy
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Science, University of Campania, Luigi Vanvitelli, 80138 Naples, Italy
- Correspondence: (T.C.); (M.G.)
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Airik M, Phua YL, Huynh AB, McCourt BT, Rush BM, Tan RJ, Vockley J, Murray SL, Dorman A, Conlon PJ, Airik R. Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1. Kidney Int 2022; 102:1042-1056. [PMID: 35931300 PMCID: PMC9588672 DOI: 10.1016/j.kint.2022.07.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 06/24/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022]
Abstract
Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage-induced CKD pathogenesis are not well understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome, karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. In vitro and in vivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression.
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Affiliation(s)
- Merlin Airik
- Division of Nephrology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yu Leng Phua
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Amy B Huynh
- Division of Nephrology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Blake T McCourt
- Division of Nephrology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Brittney M Rush
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Roderick J Tan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jerry Vockley
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Susan L Murray
- Department of Nephrology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Anthony Dorman
- Department of Nephrology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Peter J Conlon
- Department of Nephrology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Rannar Airik
- Division of Nephrology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Wang Z, Zhang C. From AKI to CKD: Maladaptive Repair and the Underlying Mechanisms. Int J Mol Sci 2022; 23:ijms231810880. [PMID: 36142787 PMCID: PMC9504835 DOI: 10.3390/ijms231810880] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 12/03/2022] Open
Abstract
Acute kidney injury (AKI) is defined as a pathological condition in which the glomerular filtration rate decreases rapidly over a short period of time, resulting in changes in the physiological function and tissue structure of the kidney. An increasing amount of evidence indicates that there is an inseparable relationship between acute kidney injury and chronic kidney disease (CKD). With the progress in research in this area, researchers have found that the recovery of AKI may also result in the occurrence of CKD due to its own maladaptation and other potential mechanisms, which involve endothelial cell injury, inflammatory reactions, progression to fibrosis and other pathways that promote the progress of the disease. Based on these findings, this review summarizes the occurrence and potential mechanisms of maladaptive repair in the progression of AKI to CKD and explores possible treatment strategies in this process so as to provide a reference for the inhibition of the progression of AKI to CKD.
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36
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Scattered Tubular Cells Markers in Macula Densa of Normal Human Adult Kidney. Int J Mol Sci 2022; 23:ijms231810504. [PMID: 36142420 PMCID: PMC9500602 DOI: 10.3390/ijms231810504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 11/28/2022] Open
Abstract
Background: The scattered tubular cells (STCs) are a population of resident progenitor tubular cells with expansion, self-renewal and epithelial differentiation abilities. Although these cells are localized within the proximal (PTs) and distal (DTs) tubules in a normal adult kidney, their presence has never been demonstrated in human macula densa (MD). The purpose of the present study is to describe the presence of STCs in MD using specific markers such as prominin-1 (CD133), cytokeratin 7 (KRT7) and vimentin (VIM). Methods: We analyzed two sets of three consecutive serial sections for each sample. The first sections of each set were immunostained for nNOS to identify MD, the second sections were immune-stained for CD133 (specific STCs marker) while the third sections were analyzed for KRT7 (another STCs specific marker) and VIM (that stains the basal pole of the STCs) in the first and second sets, respectively, in order to study the co-expression of KRT7 and VIM with the CD133 marker. Results: CD133 was localized in some MD cells and in the adjacent DT cells. Moreover, CD133 was detected in the parietal epithelial cells of Bowman’s capsule and in some proximal tubules (PT). KRT7-positive cells were identified in MD and adjacent DT cells, while KRT7 positivity was mostly confined in both DT and collecting ducts (CD) in the other areas of the renal parenchyma. CD133 and KRT7 were co-expressed in some MD and adjacent DT cells. Some of the latter cells were positive both for CD133 and VIM. CD133 was always localized in the apical part of the cells, whereas the VIM expression was evident only in the cellular basal pole. Although some cells of MD expressed VIM or CD133, none of them co-expressed VIM and CD133. Conclusions: The presence of STCs was demonstrated in human adult MD, suggesting that this structure has expansion, self-renewal and epithelial differentiation abilities, similar to all other parts of renal tubules.
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Játiva S, Torrico S, Calle P, Muñoz Á, García M, Larque AB, Poch E, Hotter G. NGAL release from peripheral blood mononuclear cells protects against acute kidney injury and prevents AKI induced fibrosis. Biomed Pharmacother 2022; 153:113415. [DOI: 10.1016/j.biopha.2022.113415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 11/30/2022] Open
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Zhu M, Zhang Z, Chen Z, Xu Y, Wu J, Che X, Ying L, Shao X, Tang L, Zhou W, Zhang M, Zhang M, Mou S. Single-cell RNA landscape of cell fate decision of renal proximal tubular epithelial cells and immune-microenvironment in kidney fibrosis. Clin Transl Med 2022; 12:e1010. [PMID: 36082701 PMCID: PMC9460484 DOI: 10.1002/ctm2.1010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Minyan Zhu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenhua Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhejun Chen
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yao Xu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiajin Wu
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Transplantation Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiajing Che
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liang Ying
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Transplantation Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xinghua Shao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lumin Tang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenyan Zhou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Minfang Zhang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Transplantation Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shan Mou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Okumura K, Grace H, Sogawa H, Yamanaga S. Acute kidney injury and the compensation of kidney function after nephrectomy in living donation. World J Transplant 2022; 12:223-230. [PMID: 36159072 PMCID: PMC9453297 DOI: 10.5500/wjt.v12.i8.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/27/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) incidence is growing rapidly, and AKI is one of the predictors of inpatient mortality. After nephrectomy, all the patients have decreased kidney function with AKI and recover from AKI. However, the characteristic and behavior of AKI is different from usual AKI and compensatory kidney function has been well known in the postoperative setting, especially in living donors. In this review, we have focused on the compensation of kidney function after nephrectomy in living donors. We discuss factors that have been identified as being associated with kidney recovery in donors including age, sex, body mass index, remnant kidney volume, estimated glomerular filtration rate, and various comorbidities.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Holly Grace
- Department of Surgery, New York Medical College, Valhalla, NY 10595, United States
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto 861-8520, Japan
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40
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Rossaint J, Meersch M, Thomas K, Mersmann S, Lehmann M, Skupski J, Tekath T, Rosenberger P, Kellum JA, Pavenstädt H, Zarbock A. Remote ischemic preconditioning causes transient cell-cycle arrest and renal protection by a NF-kB-dependent Sema5B pathway. JCI Insight 2022; 7:158523. [PMID: 35727636 PMCID: PMC9431690 DOI: 10.1172/jci.insight.158523] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022] Open
Abstract
Acute kidney injury increases morbidity and mortality, and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary high mobility group box protein-1 (HMGB1) levels in patients, and this correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine, and HMGB1 binds to TLR4 on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on nonrenal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPKα and NF-κB; this induction contributes to the upregulation of Sema5b, which triggers a transient, protective G1 cell cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.
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Affiliation(s)
- Jan Rossaint
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany
| | - Melanie Meersch
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Katharina Thomas
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Sina Mersmann
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Martin Lehmann
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Jennifer Skupski
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Tobias Tekath
- Institute of Medical Informatics, University of Münster, Münster, Germany
| | - Peter Rosenberger
- Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany
| | - John A Kellum
- Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America
| | - Hermann Pavenstädt
- Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany
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Albumin-induced premature senescence in human renal proximal tubular cells and its relationship with intercellular fibrosis. Acta Biochim Biophys Sin (Shanghai) 2022; 54:893-903. [PMID: 35713317 PMCID: PMC9828402 DOI: 10.3724/abbs.2022055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The presence of senescent cells is associated with renal fibrosis. This study aims to investigate the effect of albumin-induced premature senescence on tubulointerstitial fibrosis and its possible mechanism in vitro. Different concentrations of bovine serum albumim (BSA) with or without si-p21 are used to stimulate HK-2 cells for 72 h, and SA-β-gal activity, senescence-associated secretory phenotypes (SASPs), LaminB1 are used as markers of senescence. Immunofluorescence staining is performed to characterize the G2/M phase arrest between the control and BSA groups. Alterations in the DNA damage marker γ-H2AX, fibrogenesis, and associated proteins at the G2/M phase, such as p21, p-CDC25C and p-CDK1, are evaluated. Compared with those in the control group, the SA-β-gal activity, SASP, and γ-H2AX levels are increased in the BSA group, while the level of LaminB1 is decreased. Meanwhile, HK-2 cells blocked at the G2/M phase are significantly increased under the stimulation of BSA, and the levels of p21, p-CDC25C and p-CDK1, as well as fibrogenesis are also increased. When p21 expression is inhibited, the levels of p-CDC25C and p-CDK1 are decreased and the G2/M phase arrest is improved, which decreases the production of fibrogenesis. In conclusion, BSA induces renal tubular epithelial cell premature senescence, which regulates the G2/M phase through the CDC25C/CDK1 pathway, leading to tubulointerstitial fibrosis.
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Sako K, Furuichi K, Makiishi S, Yamamura Y, Okumura T, Le T, Kitajima S, Toyama T, Hara A, Iwata Y, Sakai N, Shimizu M, Niimura F, Matsusaka T, Kaneko S, Wada T. Cyclin-dependent kinase 4-related tubular epithelial cell proliferation is regulated by Paired box gene 2 in kidney ischemia-reperfusion injury. Kidney Int 2022; 102:45-57. [PMID: 35483529 DOI: 10.1016/j.kint.2022.03.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 02/08/2022] [Accepted: 03/09/2022] [Indexed: 12/20/2022]
Abstract
Paired box 2 (Pax2) is a transcription factor essential for kidney development and is reactivated in proximal tubular epithelial cells (PTECs) during recovery from kidney injury. However, the role of Pax2 in this process is still unknown. Here the role of Pax2 reactivation during injury was examined in the proliferation of PTECs using an ischemia-reperfusion injury (IRI) mouse model. Kidney proximal tubule-specific Pax2 conditional knockout mice were generated by mating kidney androgen-regulated protein-Cre and Pax2 flox mice. The degree of cell proliferation and fibrosis was assessed and a Pax2 inhibitor (EG1) was used to evaluate the role of Pax2 in the hypoxic condition of cultured PTECs (O2 5%, 24 hours). The number of Pax2-positive cells and Pax2 mRNA increased after IRI. Sirius red staining indicated that the area of interstitial fibrosis was significantly larger in knockout mice 14 days after IRI. The number of Ki-67-positive cells (an index of proliferation) was significantly lower in knockout than in wild-type mice after IRI, whereas the number of TUNEL-positive cells (an index of apoptotic cells) was significantly higher in knockout mice four days after IRI. Expression analyses of cell cycle-related genes showed that cyclin-dependent kinase 4 (CDK4) was significantly less expressed in the Pax2 knockout mice. In vitro data showed that the increase in CDK4 mRNA and protein expression induced by hypoxia was attenuated by EG1. Thus, Pax2 reactivation may be involved in PTEC proliferation by activating CDK4, thereby limiting kidney fibrosis.
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Affiliation(s)
- Keisuke Sako
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Kengo Furuichi
- Department of Nephrology, School of Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Shohei Makiishi
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Yuta Yamamura
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Toshiya Okumura
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Thu Le
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Division of Infection Control, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Fumio Niimura
- Department of Pediatrics, School of Medicine, Tokai University, Isehara, Japan
| | - Taiji Matsusaka
- Department of Basic Medicine, School of Medicine, Tokai University, Isehara, Japan; Institute of Medical Science, Tokai University, Isehara, Japan
| | - Shuichi Kaneko
- Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
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Extracellular Vesicles Derived from Human Liver Stem Cells Attenuate Chronic Kidney Disease Development in an In Vivo Experimental Model of Renal Ischemia and Reperfusion Injury. Int J Mol Sci 2022; 23:ijms23031485. [PMID: 35163409 PMCID: PMC8835844 DOI: 10.3390/ijms23031485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
The potential therapeutic effect of extracellular vesicles (EVs) that are derived from human liver stem cells (HLSCs) has been tested in an in vivo model of renal ischemia and reperfusion injury (IRI), that induce the development of chronic kidney disease (CKD). EVs were administered intravenously immediately after the IRI and three days later, then their effect was tested at different time points to evaluate how EV-treatment might interfere with fibrosis development. In IRI-mice that were sacrificed two months after the injury, EV- treatment decreased the development of interstitial fibrosis at the histological and molecular levels. Furthermore, the expression levels of pro-inflammatory genes and of epithelial-mesenchymal transition (EMT) genes were significantly reverted by EV-treatment. In IRI-mice that were sacrificed at early time points (two and three days after the injury), functional and histological analyses showed that EV-treatment induced an amelioration of the acute kidney injury (AKI) that was induced by IRI. Interestingly, at the molecular level, a reduction of pro-fibrotic and EMT-genes in sacrificed IRI-mice was observed at days two and three after the injury. These data indicate that in renal IRI, treatment with HLSC-derived EVs improves AKI and interferes with the development of subsequent CKD by modulating the genes that are involved in fibrosis and EMT.
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Lin HC, Paul CR, Kuo C, Chang Y, Chen WS, Ho T, Day C, Velmurugan BK, Tsai Y, Huang C. Glycyrrhiza uralensis
root extract ameliorates high glucose‐induced renal proximal tubular fibrosis by attenuating tubular epithelial‐myofibroblast transdifferentiation by targeting TGF‐β1/Smad/Stat3 pathway. J Food Biochem 2022; 46:e14041. [PMID: 35064587 DOI: 10.1111/jfbc.14041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/03/2021] [Accepted: 12/09/2021] [Indexed: 02/06/2023]
Affiliation(s)
| | - Catherine Reena Paul
- Cardiovascular and Mitochondrial Related Disease Research Center Hualien Tzu Chi Hospital Hualien Taiwan
| | - Chia‐Hua Kuo
- Laboratory of Exercise Biochemistry University of Taipei Taipei Taiwan
| | - Yung‐Hsien Chang
- Department of Chinese Medicine China Medical University Hospital China Medical University Taichung Taiwan
| | - William Shao‐Tsu Chen
- Department of Psychiatry Tzu Chi General Hospital Hualien Taiwan
- School of Medicine Tzu Chi University Hualien Taiwan
| | - Tsung‐Jung Ho
- Department of Chinese Medicine Hualien Tzu Chi Hospital Tzu Chi University Hualien Taiwan
- Integration Center of Traditional Chinese and Modern Medicine HualienTzu Chi Hospital Hualien Taiwan
- School of Post‑Baccalaure‑ate Chinese Medicine College of Medicine Tzu Chi University Hualien Taiwan
| | | | | | - Yuhsin Tsai
- Graduate Institute of Chinese Medicine China Medical University Taichung Taiwan
| | - Chih‐Yang Huang
- Graduate Institute of Chinese Medicine China Medical University Taichung Taiwan
- Cardiovascular and Mitochondrial Related Disease Research Center Hualien Tzu Chi Hospital Hualien Taiwan
- Department of Biotechnology Asia University Taichung Taiwan
- Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan
- Center of General Education Tzu Chi University of Science and Technology Hualien Taiwan
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45
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Wu YS, Liang S, Li DY, Wen JH, Tang JX, Liu HF. Cell Cycle Dysregulation and Renal Fibrosis. Front Cell Dev Biol 2021; 9:714320. [PMID: 34900982 PMCID: PMC8660570 DOI: 10.3389/fcell.2021.714320] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
Precise regulation of cell cycle is essential for tissue homeostasis and development, while cell cycle dysregulation is associated with many human diseases including renal fibrosis, a common process of various chronic kidney diseases progressing to end-stage renal disease. Under normal physiological conditions, most of the renal cells are post-mitotic quiescent cells arrested in the G0 phase of cell cycle and renal cells turnover is very low. Injuries induced by toxins, hypoxia, and metabolic disorders can stimulate renal cells to enter the cell cycle, which is essential for kidney regeneration and renal function restoration. However, more severe or repeated injuries will lead to maladaptive repair, manifesting as cell cycle arrest or overproliferation of renal cells, both of which are closely related to renal fibrosis. Thus, cell cycle dysregulation of renal cells is a potential therapeutic target for the treatment of renal fibrosis. In this review, we focus on cell cycle regulation of renal cells in healthy and diseased kidney, discussing the role of cell cycle dysregulation of renal cells in renal fibrosis. Better understanding of the function of cell cycle dysregulation in renal fibrosis is essential for the development of therapeutics to halt renal fibrosis progression or promote regression.
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Affiliation(s)
- Yun-Shan Wu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shan Liang
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Dong-Yi Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jun-Hao Wen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ji-Xin Tang
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.,Shunde Women and Children's Hospital, Guangdong Medical University (Foshan Shunde Maternal and Child Healthcare Hospital), Foshan, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Parvin S, Williams CR, Jarrett SA, Garraway SM. Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages. Inflammation 2021; 44:2346-2361. [PMID: 34417952 PMCID: PMC8616867 DOI: 10.1007/s10753-021-01507-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/21/2021] [Indexed: 11/26/2022]
Abstract
Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.
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Affiliation(s)
- Shangrila Parvin
- Department of Physiology, Emory University School of Medicine, 615 Michael Street, Suite 605G, Atlanta, GA 30322 USA
| | - Clintoria R. Williams
- Department of Physiology, Emory University School of Medicine, 615 Michael Street, Suite 605G, Atlanta, GA 30322 USA
- Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH USA
| | - Simone A. Jarrett
- Department of Physiology, Emory University School of Medicine, 615 Michael Street, Suite 605G, Atlanta, GA 30322 USA
| | - Sandra M. Garraway
- Department of Physiology, Emory University School of Medicine, 615 Michael Street, Suite 605G, Atlanta, GA 30322 USA
- Department of Physiology, Emory University School of Medicine, 615 Michael Street, Suite 605G, Atlanta, GA 30322 USA
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Hanai S, Uchimura K, Takahashi K, Ishii T, Mitsui T, Furuya F. Hypoxia-induced thyroid hormone receptor expression regulates cell-cycle progression in renal tubule epithelial cells. Endocr J 2021; 68:1309-1320. [PMID: 34108302 DOI: 10.1507/endocrj.ej21-0245] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Hypoxia occurs in the kidneys of chronic kidney disease (CKD) patients, inducing interstitial fibrosis and tubule cell death. Renal tubule cell death is an important determinant of mortality in CKD. We focused on the regulation of cell-cycle-mediated protein expression to prevent cell death under chronic hypoxia in the kidneys of CKD patients. Paraffin-embedded kidney sections from patients with CKD (diabetes nephropathy, nephrosclerosis, or IgA nephropathy) were analyzed for the expression of hypoxia-inducible factor (HIF), thyroid hormone receptor (TR) β, or p21 and levels of interstitial fibrosis. Human renal proximal tubule cells were exposed to hypoxia and analyzed for the expression of HIF, TRβ, or p21 and the cell-cycle stage. TRβ expression was enhanced early on when fibrosis was not fully developed in the tubule cells of CKD patients. HIF1α bound to the TRβ promoter and directly induced its transcription. Further, HIF1α expression induced the expression of TRβ and inhibited cell-cycle progression. In the early stage of kidney injury, TRβ might act as a guardian to prepare and organize cell-cycle proliferation and prevent cell death. While the molecular mechanism that regulates the expression of cell-cycle regulators in renal tubule cells remains controversial, TRβ has strong potential as a new therapeutic target.
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Affiliation(s)
- Shunichiro Hanai
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Kohei Uchimura
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Kazuya Takahashi
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Toshihisa Ishii
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Takahiko Mitsui
- Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Fumihiko Furuya
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan
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Moreno JCA, Bahmad HF, Febres-Aldana CA, Pirela A, Azuero A, Salami A, Poppiti R. Post-mortem assessment of vimentin expression as a biomarker for renal tubular regeneration following acute kidney injury. J Pathol Transl Med 2021; 55:369-379. [PMID: 34638220 PMCID: PMC8601956 DOI: 10.4132/jptm.2021.08.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/03/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a common cause of morbidity and mortality. It mainly targets the renal tubular epithelium with pathological changes, referred to as acute tubular injury. The latter is followed by a regenerative response that is difficult to visualize on routine hematoxylin and eosin (H&E) stains. In this study, we examined the regenerative capacity of renal tubules by correlating vimentin (VIM) immunohistochemical (IHC) expression and pathological findings of AKI and renal tubular regeneration (RTR) on H&E. METHODS We reviewed 23 autopsies performed in the clinical setting of AKI and RTR. VIM expression was scored in the renal cortical tubular epithelium using a statistical cutoff ≥ 3% for high expression and < 3% for low expression. RESULTS Of the 23 kidney tissues examined, seven (30.4%) had low VIM expression, and 16 (69.6%) had high VIM expression. Kidney tissues with evidence of AKI and RTR had significantly higher VIM expression. Renal peritubular microenvironment features showing regenerative changes on H&E were associated with high VIM expression. In the univariate model, kidney tissues with RTR were 18-fold more likely to have high VIM expression. CONCLUSIONS In conclusion, our findings suggest that VIM could serve as an IHC marker for RTR following AKI. However, correlation with H&E findings remains critical to excluding chronic tubular damage. Collectively, our preliminary results pave the way for future studies including a larger sample size to validate the use of VIM as a reliable biomarker for RTR.
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Affiliation(s)
- Juan Carlos Alvarez Moreno
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Hisham F Bahmad
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Christopher A Febres-Aldana
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Andrés Pirela
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Andres Azuero
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Ali Salami
- Department of Mathematics, Faculty of Sciences, Lebanese University, Nabatieh, Lebanon
| | - Robert Poppiti
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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49
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Little MH, Howden SE, Lawlor KT, Vanslambrouck JM. Determining lineage relationships in kidney development and disease. Nat Rev Nephrol 2021; 18:8-21. [PMID: 34594045 DOI: 10.1038/s41581-021-00485-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2021] [Indexed: 12/17/2022]
Abstract
The lineage relationships of cells provide information about the origins of component cell types during development and repair as well as the source of aberrant cells during disease. Genetic approaches to lineage tracing applied in the mouse have revealed much about how the mammalian kidney forms, including the identification of key progenitors for the nephrons and stromal compartments. Inducible Cre systems have also facilitated lineage tracing studies in the postnatal animal that illustrate the changes in cellular fate that can occur during kidney injury. With the advent of single-cell transcriptional profiling and trajectory analyses, predictions of cellular relationships across development are now being made in model systems, such as the mouse, as well as in human fetal kidney. Importantly, these approaches provide predictions of lineage relationships rather than definitive evidence. Although genetic approaches to the study of lineage have not previously been possible in a human setting, the application of CRISPR-Cas9 gene editing of pluripotent stem cells is beginning to teach us about human lineage relationships.
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Affiliation(s)
- Melissa H Little
- Murdoch Children's Research Institute, Parkville, VIC, Australia. .,Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia. .,Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia.
| | - Sara E Howden
- Murdoch Children's Research Institute, Parkville, VIC, Australia.,Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
| | - Kynan T Lawlor
- Murdoch Children's Research Institute, Parkville, VIC, Australia
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Smart L, Boyd C, Litton E, Pavey W, Vlaskovsky P, Ali U, Mori T, Barden A, Ho KM. A randomised controlled trial of succinylated gelatin (4%) fluid on urinary acute kidney injury biomarkers in cardiac surgical patients. Intensive Care Med Exp 2021; 9:48. [PMID: 34549356 PMCID: PMC8455786 DOI: 10.1186/s40635-021-00412-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 08/13/2021] [Indexed: 11/10/2022] Open
Abstract
Background Fluid resuscitation is frequently required for cardiac surgical patients admitted to the intensive care unit. The ideal fluid of choice in regard to efficacy and safety remains uncertain. Compared with crystalloid fluid, colloid fluid may result in less positive fluid balance. However, some synthetic colloids are associated with increased risk of acute kidney injury (AKI). This study compared the effects of succinylated gelatin (4%) (GEL) with compound sodium lactate (CSL) on urinary AKI biomarkers in patients after cardiac surgery. Methods Cardiac surgical patients who required an intravenous fluid bolus of at least 500 mL postoperatively were randomly allocated to receive GEL or CSL as the resuscitation fluid of choice for the subsequent 24 h. Primary outcomes were serial urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C concentrations measured at baseline, 1 h, 5 h and 24 h after enrolment, with higher concentrations indicating greater kidney injury. Secondary biomarker outcomes included urinary clusterin, α1-microglobulin and F2-isoprostanes concentrations. Differences in change of biomarker concentration between the two groups over time were compared with mixed-effects regression models. Statistical significance was set at P < 0.05. Results Forty cardiac surgical patients (n = 20 per group) with similar baseline characteristics were included. There was no significant difference in the median volume of fluid boluses administered over 24 h between the GEL (1250 mL, Q1–Q3 500–1750) and CSL group (1000 mL, Q1–Q3 500–1375) (P = 0.42). There was a significantly greater increase in urinary cystatin C (P < 0.001), clusterin (P < 0.001), α1-microglobulin (P < 0.001) and F2-isoprostanes (P = 0.020) concentrations over time in the GEL group, compared to the CSL group. Change in urinary NGAL concentration (P = 0.68) over time was not significantly different between the groups. The results were not modified by adjustment for either urinary osmolality or EuroSCORE II predicted risk of mortality. Conclusions This preliminary randomised controlled trial showed that use of succinylated gelatin (4%) for fluid resuscitation after cardiac surgery was associated with increased biomarker concentrations of renal tubular injury and dysfunction, compared to crystalloid fluid. These results generate concern that use of intravenous gelatin fluid may contribute to clinically relevant postoperative AKI. Trial registration ANZCTR.org.au, ACTRN12617001461381. Registered on 16th October, 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373619&isReview=true. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-021-00412-9.
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Affiliation(s)
- Lisa Smart
- College of Science, Health, Engineering and Education, Murdoch University, South St, Murdoch, WA, 6150, Australia. .,Centre for Clinical Research in Emergency Medicine, Perth, Australia.
| | - Corrin Boyd
- College of Science, Health, Engineering and Education, Murdoch University, South St, Murdoch, WA, 6150, Australia
| | - Edward Litton
- Intensive Care Unit, Fiona Stanley Hospital, Murdoch, Australia.,Intensive Care Unit, St John of God Hospital, Subiaco, Australia
| | - Warren Pavey
- College of Science, Health, Engineering and Education, Murdoch University, South St, Murdoch, WA, 6150, Australia.,Department of Anaesthesia, Fiona Stanley Hospital, Murdoch, Australia
| | | | - Umar Ali
- Department of Cardiothoracic Surgery and Transplantation, Fiona Stanley Hospital, Murdoch, Australia
| | - Trevor Mori
- Medical School, University of Western Australia, Perth, Australia
| | - Anne Barden
- Medical School, University of Western Australia, Perth, Australia
| | - Kwok Ming Ho
- College of Science, Health, Engineering and Education, Murdoch University, South St, Murdoch, WA, 6150, Australia.,Medical School, University of Western Australia, Perth, Australia.,Intensive Care Unit, Royal Perth Hospital, Perth, Australia
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