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1
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Ansari A, Walton SL, Denton KM. Sex- and age-related differences in renal and cardiac injury and senescence in stroke-prone spontaneously hypertensive rats. Biol Sex Differ 2023; 14:33. [PMID: 37217968 DOI: 10.1186/s13293-023-00519-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/05/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND Sex differences play a critical role in the incidence and severity of cardiovascular diseases, whereby men are at a higher risk of developing cardiovascular disease compared to age-matched premenopausal women. Marked sex differences at the cellular and tissue level may contribute to susceptibility to cardiovascular disease and end-organ damage. In this study, we have performed an in-depth histological analysis of sex differences in hypertensive cardiac and renal injury in middle-aged stroke-prone spontaneously hypertensive rats (SHRSPs) to determine the interaction between age, sex and cell senescence. METHODS Kidneys, hearts and urine samples were collected from 6.5- and 8-month-old (Mo) male and female SHRSPs. Urine samples were assayed for albumin and creatinine content. Kidneys and hearts were screened for a suite of cellular senescence markers (senescence-associated β-galactosidase, p16INK4a, p21, γH2AX). Renal and cardiac fibrosis was quantified using Masson's trichrome staining, and glomerular hypertrophy and sclerosis were quantified using Periodic acid-Schiff staining. RESULTS Marked renal and cardiac fibrosis, concomitant with albuminuria, were evident in all SHRSPs. These sequelae were differentially affected by age, sex and organ. That is, the level of fibrosis was greater in the kidney than the heart, males had greater levels of fibrosis than females in both the heart and kidney, and even a 6-week increase in age resulted in greater levels of kidney fibrosis in males. The differences in kidney fibrosis were reflected by elevated levels of cellular senescence in the kidney in males but not females. Senescent cell burden was significantly less in cardiac tissue compared to renal tissue and was not affected by age or sex. CONCLUSIONS Our study demonstrates a clear sex pattern in age-related progression of renal and cardiac fibrosis and cellular senescence in SHRSP rats. A 6-week time frame was associated with increased indices of cardiac and renal fibrosis and cellular senescence in male SHRSPs. Female SHRSP rats were protected from renal and cardiac damage compared to age-matched males. Thus, the SHRSP is an ideal model to investigate the effects of sex and aging on organ injury over a short timeframe.
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Affiliation(s)
- Aneesa Ansari
- Department of Physiology, Monash University, Melbourne, VIC, Australia
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Sarah L Walton
- Department of Physiology, Monash University, Melbourne, VIC, Australia
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Kate M Denton
- Department of Physiology, Monash University, Melbourne, VIC, Australia.
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
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2
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Novel Insights in the Physiopathology and Management of Obesity-Related Kidney Disease. Nutrients 2022; 14:nu14193937. [PMID: 36235590 PMCID: PMC9572176 DOI: 10.3390/nu14193937] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/30/2022] Open
Abstract
Obesity is recognized as an independent risk factor for the development of kidney disease, which has led to the designation of obesity-related glomerulopathy (ORG). Common renal features observed in this condition include glomerular hypertrophy, glomerulosclerosis, haemodynamic changes and glomerular filtration barrier defects. Additionally, and although less studied, obesity-related kidney disease also involves alterations in renal tubules, including tubule hypertrophy, lipid deposition and tubulointerstitial fibrosis. Although not completely understood, the harmful effects of obesity on the kidney may be mediated by different mechanisms, with alterations in adipose tissue probably playing an important role. An increase in visceral adipose tissue has classically been associated with the development of kidney damage, however, recent studies point to adipose tissue surrounding the kidney, and specifically to the fat within the renal sinus, as potentially involved in the development of ORG. In addition, new strategies for the treatment of patients with obesity-related kidney disease are focusing on the management of obesity. In this regard, some non-invasive options, such as glucagon-like peptide-1 (GLP-1) receptor agonists or sodium–glucose cotransporter-2 (SGLT2) inhibitors, are being considered for application in the clinic, not only for patients with diabetic kidney disease but as a novel pharmacological strategy for patients with ORG. In addition, bariatric surgery stands as one of the most effective options, not only for weight loss but also for the improvement of kidney outcomes in obese patients with chronic kidney disease.
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3
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Wang H, Tang C, Dang ZH, Yong A, Liu L, Wang S, Zhao M. Clinicopathological characteristics of high-altitude polycythemia-related kidney disease in Tibetan inhabitants. Kidney Int 2022; 102:196-206. [PMID: 35513124 DOI: 10.1016/j.kint.2022.03.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/04/2022] [Accepted: 03/29/2022] [Indexed: 11/27/2022]
Abstract
High-altitude polycythemia (HAPC) is a clinical syndrome that occurs in native inhabitants or long-term residents living at altitude. The kidney is one of the most affected organs. However, the clinical and kidney histopathological profiles of HAPC-related kidney disease have rarely been reported. Here, we report kidney biopsy-based clinicopathological study on this disease. HAPC was defined as excessive erythrocytosis [females, hemoglobin 190 g/L or more; males, 210 g/L or more] in patients living above an altitude of 2500 m for more than ten years. A total of 416 Tibetan patients underwent kidney biopsy between January 1, 2016, and November 31, 2020. Of these patients 17 met the diagnostic criteria for HAPC-related kidney disease. Clinically, these patients had a median urinary protein level of 2.5 g/24-hour (range 1.81-6.85). Twelve patients had hyperuricemia, nine had hypertension, and three had kidney insufficiency. On histopathology, glomerular hypertrophy, glomerular basement membrane thickening, podocyte foot process effacement, segmental glomerulosclerosis and global glomerulosclerosis were the main features. Extraglomerular arterial/arteriolar lesions were common, presenting as intimal fibrosis, hyalinosis and endothelial cell swelling/subintimal edema. Expansion of the arterial/arteriolar medial wall area characterized by smooth muscle cell proliferation was clearly observed, potentially indicating vascular remodeling. Hypoxia-inducible factor 2α was expressed in the kidney tissues of these patients. Thus, the pathological changes of HAPC-related kidney disease encompassed both glomerular and extraglomerular vascular lesions, suggesting a key role of both chronic hypoxia itself and secondary hemodynamic changes in the pathogenesis of this disease.
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Affiliation(s)
- Hui Wang
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, P.R. China; Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing 100034, P.R. China
| | - Chen Tang
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, P.R. China
| | - Zong-Hui Dang
- The People's Hospital of Tibet Autonomous region, Lhasa, Tibet, P.R. China
| | - A Yong
- The People's Hospital of Tibet Autonomous region, Lhasa, Tibet, P.R. China
| | - Lijun Liu
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, P.R. China.
| | - Suxia Wang
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, P.R. China; Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing 100034, P.R. China.
| | - Minghui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, P.R. China
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4
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Qi C, Alsomali F, Zhong J, Harris RC, Kon V, Yang H, Fogo AB. Increased dishevelled associated activator of morphogenesis 2, a new podocyte-associated protein, in diabetic nephropathy. Nephrol Dial Transplant 2021; 36:1006-1016. [PMID: 33544843 DOI: 10.1093/ndt/gfab014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 01/05/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Previously, by using proteomic analysis and RNA sequencing in isolated glomeruli, we identified several novel differentially expressed proteins in human and mouse diabetic nephropathy (DN) versus controls, including dishevelled associated activator of morphogenesis 2 (DAAM2). DAAM2 binds the Wnt effector Dvl. We aimed to study possible contributions of DAAM2 to DN. METHODS We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal donor kidney tissues. We also examined DAAM2 in DN mice (db/db eNOS-/-) and Nx mice. DN mice treated with angiotensin-converting enzyme inhibitor (ACEI), dipeptidyl peptidase 4 inhibitor (DPP4I) or vehicle were compared. DAAM2 was knocked down in primary cultured podocytes by small interfering RNA to study its effects on cell function. RESULTS In normal human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both Nx and DN versus normal donors. Podocyte DAAM2 expression was increased in DN and Nx mouse models. Glomerular DAAM2 expression correlated with glomerular size and was decreased significantly by ACEI while DPP4I only numerically reduced DAAM2. In primary cultured podocytes, knockdown of DAAM2 enhanced adhesion, slowed migration, activated Wnt-β-catenin signaling and downregulated mammalian target of rapamycin complex 1 (mTORC1) and Rho activity. CONCLUSIONS Podocyte DAAM2 is upregulated in both Nx and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.
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Affiliation(s)
- Chenyang Qi
- Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Faten Alsomali
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Jinyong Zhong
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.,Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Raymond C Harris
- Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Valentina Kon
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Haichun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.,Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.,Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA.,Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
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5
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Ngowi EE, Sarfraz M, Afzal A, Khan NH, Khattak S, Zhang X, Li T, Duan SF, Ji XY, Wu DD. Roles of Hydrogen Sulfide Donors in Common Kidney Diseases. Front Pharmacol 2020; 11:564281. [PMID: 33364941 PMCID: PMC7751760 DOI: 10.3389/fphar.2020.564281] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/30/2020] [Indexed: 12/15/2022] Open
Abstract
Hydrogen sulfide (H2S) plays a key role in the regulation of physiological processes in mammals. The decline in H2S level has been reported in numerous renal disorders. In animal models of renal disorders, treatment with H2S donors could restore H2S levels and improve renal functions. H2S donors suppress renal dysfunction by regulating autophagy, apoptosis, oxidative stress, and inflammation through multiple signaling pathways, such as TRL4/NLRP3, AMP-activated protein kinase/mammalian target of rapamycin, transforming growth factor-β1/Smad3, extracellular signal-regulated protein kinases 1/2, mitogen-activated protein kinase, and nuclear factor kappa B. In this review, we summarize recent developments in the effects of H2S donors on the treatment of common renal diseases, including acute/chronic kidney disease, renal fibrosis, unilateral ureteral obstruction, glomerulosclerosis, diabetic nephropathy, hyperhomocysteinemia, drug-induced nephrotoxicity, metal-induced nephrotoxicity, and urolithiasis. Novel H2S donors can be designed and applied in the treatment of common renal diseases.
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Affiliation(s)
- Ebenezeri Erasto Ngowi
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Department of Biological Sciences, Faculty of Science, Dar es Salaam University College of Education, Dar es Salaam, Tanzania
| | - Muhammad Sarfraz
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, China
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Attia Afzal
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- College of Pharmacy, Henan University, Kaifeng, China
| | - Saadullah Khattak
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Xin Zhang
- College of Pharmacy, Henan University, Kaifeng, China
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Tao Li
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Shao-Feng Duan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- College of Pharmacy, Henan University, Kaifeng, China
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Xin-Ying Ji
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Diseases and Bio-Safety, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Dong-Dong Wu
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- School of Stomatology, Henan University, Kaifeng, China
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6
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Bruggeman LA, Wu Z, Luo L, Madhavan S, Drawz PE, Thomas DB, Barisoni L, O'Toole JF, Sedor JR. APOL1-G0 protects podocytes in a mouse model of HIV-associated nephropathy. PLoS One 2019; 14:e0224408. [PMID: 31661509 PMCID: PMC6818796 DOI: 10.1371/journal.pone.0224408] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/11/2019] [Indexed: 11/21/2022] Open
Abstract
African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.
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Affiliation(s)
- Leslie A. Bruggeman
- Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- * E-mail:
| | - Zhenzhen Wu
- Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Liping Luo
- Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Sethu Madhavan
- Department of Medicine, Ohio State University, Columbus, Ohio, United States of America
| | - Paul E. Drawz
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - David B. Thomas
- Departments of Pathology, University of Miami, Miami, Florida, United States of America
| | - Laura Barisoni
- Departments of Pathology and Medicine, Duke University, Durham, North Carolina, United States of America
| | - John F. O'Toole
- Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - John R. Sedor
- Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
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7
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Puelles VG, van der Wolde JW, Wanner N, Scheppach MW, Cullen-McEwen LA, Bork T, Lindenmeyer MT, Gernhold L, Wong MN, Braun F, Cohen CD, Kett MM, Kuppe C, Kramann R, Saritas T, van Roeyen CR, Moeller MJ, Tribolet L, Rebello R, Sun YB, Li J, Müller-Newen G, Hughson MD, Hoy WE, Person F, Wiech T, Ricardo SD, Kerr PG, Denton KM, Furic L, Huber TB, Nikolic-Paterson DJ, Bertram JF. mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI Insight 2019; 4:99271. [PMID: 31534053 DOI: 10.1172/jci.insight.99271] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 08/08/2019] [Indexed: 02/06/2023] Open
Abstract
The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.
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Affiliation(s)
- Victor G Puelles
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.,Department of Nephrology, Monash Health, Melbourne, Australia.,Center for Inflammatory Diseases, Monash University, Melbourne, Australia.,III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - James W van der Wolde
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Nicola Wanner
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Luise A Cullen-McEwen
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Tillmann Bork
- Renal Division, University Medical Center Freiburg, Freiburg, Germany
| | - Maja T Lindenmeyer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lukas Gernhold
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Milagros N Wong
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fabian Braun
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Clemens D Cohen
- Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany
| | - Michelle M Kett
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia
| | | | | | | | | | | | - Leon Tribolet
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Richard Rebello
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Yu By Sun
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Jinhua Li
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Gerhard Müller-Newen
- Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany
| | - Michael D Hughson
- Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Wendy E Hoy
- Centre for Chronic Disease, The University of Queensland, Brisbane, Queensland, Australia
| | - Fermin Person
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Wiech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sharon D Ricardo
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Peter G Kerr
- Department of Nephrology, Monash Health, Melbourne, Australia.,Center for Inflammatory Diseases, Monash University, Melbourne, Australia
| | - Kate M Denton
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia
| | - Luc Furic
- Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia.,Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David J Nikolic-Paterson
- Department of Nephrology, Monash Health, Melbourne, Australia.,Center for Inflammatory Diseases, Monash University, Melbourne, Australia
| | - John F Bertram
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
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8
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Lee JY, Yang JW, Han BG, Choi SO, Kim JS. Adiponectin for the treatment of diabetic nephropathy. Korean J Intern Med 2019; 34:480-491. [PMID: 31048658 PMCID: PMC6506734 DOI: 10.3904/kjim.2019.109] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 04/13/2019] [Indexed: 12/12/2022] Open
Abstract
The metabolic burden caused by hyperglycemia can result in direct and immediate metabolic injuries, such as oxidative stress and tissue inflammation, in the kidney. Furthermore, chronic hyperglycemia can lead to substantial structural changes such as formation of advanced glycation end-products, glomerular and tubular hypertrophy, and tissue fibrosis. Glomerular hypertrophy renders podocytes vulnerable to increased glomerular filtration, leading to podocyte instability and loss. Thus, prevention of glomerular hypertrophy and attenuation of glomerular hyperfiltration may have therapeutic potential for diabetic nephropathy (DN). Adiponectin is an adipokine that improves insulin sensitivity in obesity-related metabolic disorders, including diabetes, but its efficacy is unknown. Moreover, the recently developed adiponectin receptor agonist, AdipoRon, shows therapeutic potential for DN. In this review, we focus on the role of glomerular hypertrophy in the pathogenesis of DN and discuss the role of adiponectin in its prevention.
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Affiliation(s)
- Jun Young Lee
- Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Won Yang
- Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Byoung Geun Han
- Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seung Ok Choi
- Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seok Kim
- Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Correspondence to Jae Seok Kim, M.D. Division of Nephrology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: +82-33-741-0509 Fax: +82-33-731-5884 E-mail:
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9
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Lazzeri E, Angelotti ML, Conte C, Anders HJ, Romagnani P. Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation. Trends Mol Med 2019; 25:366-381. [PMID: 30935780 DOI: 10.1016/j.molmed.2019.02.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 02/09/2019] [Accepted: 02/13/2019] [Indexed: 12/20/2022]
Abstract
In acute organ failure, rapid compensation of function loss assures survival. Dedifferentiation and/or proliferation of surviving parenchymal cells could imply a transient (and potentially fatal) impairment of residual functional performance. However, evolution has selected two flexible life-saving mechanisms acting synergistically on organ function recovery. Sustaining residual performance is possible when the remnant differentiated parenchymal cells avoid cell division, but increase function by undergoing hypertrophy via endoreplication, leading to polyploid cells. In addition, tissue progenitors, representing a subset of less-differentiated and/or self-renewing parenchymal cells completing cytokinesis, proliferate and differentiate to regenerate lost parenchymal cells. Here, we review the evolving evidence on polyploidization and progenitor-driven regeneration in acute liver, heart, and kidney failure with evolutionary advantages and trade-offs in organ repair.
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Affiliation(s)
- Elena Lazzeri
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Maria Lucia Angelotti
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Carolina Conte
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Hans-Joachim Anders
- Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany
| | - Paola Romagnani
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE); Meyer Children's Hospital, Florence, Italy. http://www.twitter.com/PRomagnani
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10
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Glomeruli from patients with nephrin mutations show increased number of ciliated and poorly differentiated podocytes. Acta Histochem 2018; 120:748-756. [PMID: 30193978 DOI: 10.1016/j.acthis.2018.08.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/26/2018] [Accepted: 08/29/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Podocytes are postmitotic, highly specialized cells which maintain the glomerular filtration barrier (GFB). Their injury is characterized by foot processes effacement and change in protein expression leading to proteinuria and end-stage kidney disease. METHODS Our study focuses on the morphological and immunohistochemical changes of human podocytes during normal development and postnatal period, compared to congenital nephrotic syndrome of the Finnish type (CNF). Kidney tissues taken from 17 human conceptuses 8th-38th weeks old, two healthy and three CNF kidneys were embedded in paraffin for immunohistochemical or double immunofluorescence methods, or were embedded in resin for electron microscopy. Paraffin sections were stained with markers for proliferation (Ki-67), proteins nephrin and nestin, and alpha-tubulin. Quantification of positive cells were performed using Mann Whitney and Kruskal-Wallis test. RESULTS Tissue analysis showed that proliferation of podocytes gradually decreased during development and disappeared in postnatal period. Decrease in number of ciliated glomerular cells and visceral podocytes (from 47% to 3%), and parietal epithelial cells (from 32% to 7%) characterized normal development. Nestin and nephrin co-expressed in developing podocytes in different cellular compartments. During development, nephrin expression increased (from 17% to 75%) and postnatally changed its pattern, while nestin positive glomerular cells decreased from 98% to 40%. CNF glomeruli displayed increased number of immature ciliated podocytes (6%) and parietal epithelial cells (9%). CONCLUSION Changes in cytoplasmic alpha-tubulin expression and reduced nephrin expression (20%) indicating association of incomplete podocyte maturation with failure of GFB function and appearance of prenatal proteinuria in CNF patients.
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11
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Nishizono R, Kikuchi M, Wang SQ, Chowdhury M, Nair V, Hartman J, Fukuda A, Wickman L, Hodgin JB, Bitzer M, Naik A, Wiggins J, Kretzler M, Wiggins RC. FSGS as an Adaptive Response to Growth-Induced Podocyte Stress. J Am Soc Nephrol 2017; 28:2931-2945. [PMID: 28720684 DOI: 10.1681/asn.2017020174] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/08/2017] [Indexed: 11/03/2022] Open
Abstract
Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.
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Affiliation(s)
- Ryuzoh Nishizono
- Departments of Internal Medicine.,Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Masao Kikuchi
- Departments of Internal Medicine.,Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | | | | | | | | | - Akihiro Fukuda
- Departments of Internal Medicine.,Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
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12
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Mukhi D, Nishad R, Menon RK, Pasupulati AK. Novel Actions of Growth Hormone in Podocytes: Implications for Diabetic Nephropathy. Front Med (Lausanne) 2017; 4:102. [PMID: 28748185 PMCID: PMC5506074 DOI: 10.3389/fmed.2017.00102] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 06/26/2017] [Indexed: 02/05/2023] Open
Abstract
The kidney regulates water, electrolyte, and acid-base balance and thus maintains body homeostasis. The kidney's potential to ensure ultrafiltered and almost protein-free urine is compromised in various metabolic and hormonal disorders such as diabetes mellitus (DM). Diabetic nephropathy (DN) accounts for ~20-40% of mortality in DM. Proteinuria, a hallmark of renal glomerular diseases, indicates injury to the glomerular filtration barrier (GFB). The GFB is composed of glomerular endothelium, basement membrane, and podocytes. Podocytes are terminally differentiated epithelial cells with limited ability to replicate. Podocyte shape and number are both critical for the integrity and function of the GFB. Podocytes are vulnerable to various noxious stimuli prevalent in a diabetic milieu that could provoke podocytes to undergo changes to their unique architecture and function. Effacement of podocyte foot process is a typical morphological alteration associated with proteinuria. The dedifferentiation of podocytes from epithelial-to-mesenchymal phenotype and consequential loss results in proteinuria. Poorly controlled type 1 DM is associated with elevated levels of circulating growth hormone (GH), which is implicated in the pathophysiology of various diabetic complications including DN. Recent studies demonstrate that functional GH receptors are expressed in podocytes and that GH may exert detrimental effects on the podocyte. In this review, we summarize recent advances that shed light on actions of GH on the podocyte that could play a role in the pathogenesis of DN.
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Affiliation(s)
- Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Rajkishor Nishad
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Ram K. Menon
- Department of Pediatric Endocrinology and Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Anil Kumar Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
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13
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Kroeger PT, Drummond BE, Miceli R, McKernan M, Gerlach GF, Marra AN, Fox A, McCampbell KK, Leshchiner I, Rodriguez-Mari A, BreMiller R, Thummel R, Davidson AJ, Postlethwait J, Goessling W, Wingert RA. The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 2017; 428:148-163. [PMID: 28579318 DOI: 10.1016/j.ydbio.2017.05.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 12/28/2022]
Abstract
The zebrafish kidney is conserved with other vertebrates, making it an excellent genetic model to study renal development. The kidney collects metabolic waste using a blood filter with specialized epithelial cells known as podocytes. Podocyte formation is poorly understood but relevant to many kidney diseases, as podocyte injury leads to progressive scarring and organ failure. zeppelin (zep) was isolated in a forward screen for kidney mutants and identified as a homozygous recessive lethal allele that causes reduced podocyte numbers, deficient filtration, and fluid imbalance. Interestingly, zep mutants had a larger interrenal gland, the teleostean counterpart of the mammalian adrenal gland, which suggested a fate switch with the related podocyte lineage since cell proliferation and cell death were unchanged within the shared progenitor field from which these two identities arise. Cloning of zep by whole genome sequencing (WGS) identified a splicing mutation in breast cancer 2, early onset (brca2)/fancd1, which was confirmed by sequencing of individual fish. Several independent brca2 morpholinos (MOs) phenocopied zep, causing edema, reduced podocyte number, and increased interrenal cell number. Complementation analysis between zep and brca2ZM_00057434 -/- zebrafish, which have an insertional mutation, revealed that the interrenal lineage was expanded. Importantly, overexpression of brca2 rescued podocyte formation in zep mutants, providing critical evidence that the brca2 lesion encoded by zep specifically disrupts the balance of nephrogenesis. Taken together, these data suggest for the first time that brca2/fancd1 is essential for vertebrate kidney ontogeny. Thus, our findings impart novel insights into the genetic components that impact renal development, and because BRCA2/FANCD1 mutations in humans cause Fanconi anemia and several common cancers, this work has identified a new zebrafish model to further study brca2/fancd1 in disease.
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Affiliation(s)
- Paul T Kroeger
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Bridgette E Drummond
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rachel Miceli
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Michael McKernan
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Gary F Gerlach
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Amanda N Marra
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Annemarie Fox
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Kristen K McCampbell
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Ignaty Leshchiner
- Brigham and Women's Hospital, Genetics and Gastroenterology Division, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | | | - Ruth BreMiller
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Ryan Thummel
- Departments of Anatomy and Cell Biology and Opthamology, Wayne State University School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Alan J Davidson
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, NZ
| | - John Postlethwait
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Wolfram Goessling
- Brigham and Women's Hospital, Genetics and Gastroenterology Division, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA.
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14
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Puelles VG, Bertram JF, Moeller MJ. Quantifying podocyte depletion: theoretical and practical considerations. Cell Tissue Res 2017; 369:229-236. [DOI: 10.1007/s00441-017-2630-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/21/2017] [Indexed: 10/19/2022]
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15
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Podocyte number and density changes during early human life. Pediatr Nephrol 2017; 32:823-834. [PMID: 28028615 PMCID: PMC5368211 DOI: 10.1007/s00467-016-3564-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/30/2016] [Accepted: 11/30/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Podocyte depletion, which drives progressive glomerulosclerosis in glomerular diseases, is caused by a reduction in podocyte number, size or function in the context of increasing glomerular volume. METHODS Kidneys obtained at autopsy from premature and mature infants who died in the first year of life (n = 24) were used to measure podometric parameters for comparison with previously reported data from older kidneys. RESULTS Glomerular volume increased 4.6-fold from 0.13 ± 0.07 μm3 x106 in the pre-capillary loop stage, through 0.35 μm3 x106 at the capillary loop, to 0.60 μm3 x106 at the mature glomerular stage. Podocyte number per glomerulus increased from 326 ± 154 per glomerulus at the pre-capillary loop stage to 584 ± 131 per glomerulus at the capillary loop stage of glomerular development to reach a value of 589 ± 166 per glomerulus in mature glomeruli. Thus, the major podocyte number increase occurs in the early stages of glomerular development, in contradistinction to glomerular volume increase, which continues after birth in association with body growth. CONCLUSIONS As glomeruli continue to enlarge, podocyte density (number per volume) rapidly decreases, requiring a parallel rapid increase in podocyte size that allows podocyte foot processes to maintain complete coverage of the filtration surface area. Hypertrophic stresses on the glomerulus and podocyte during development and early rapid growth periods of life are therefore likely to play significant roles in determining how and when defects in podocyte structure and function due to genetic variants become clinically manifest. Therapeutic strategies aimed at minimizing mismatch between these factors may prove clinically useful.
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16
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Blutke A, Schneider MR, Wolf E, Wanke R. Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth. Physiol Rep 2016; 4:4/5/e12709. [PMID: 26997624 PMCID: PMC4823598 DOI: 10.14814/phy2.12709] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Growth hormone (GH)‐transgenic mice with permanently elevated systemic levels of GH and insulin‐like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1‐dependent and ‐independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1‐deficient (I−/−) and of IGF1‐deficient GH‐transgenic mice (I−/−/G), as well as of GH‐transgenic (G) and nontransgenic wild‐type control mice (I+/+) were examined by quantitative stereological and functional analyses. Both G and I−/−/G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I−/−/G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I+/+ mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I−/−/G mice did not display significant PTE cell hyperplasia, as compared to I−/− mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH‐dependent proximal tubular growth in GH‐transgenic mice.
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Affiliation(s)
- Andreas Blutke
- Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University Muenchen, Munich, Germany
| | - Marlon R Schneider
- Chair for Molecular Animal Breeding and Biotechnology, Gene Centre Ludwig-Maximilians-University Muenchen, Munich, Germany
| | - Eckhard Wolf
- Chair for Molecular Animal Breeding and Biotechnology, Gene Centre Ludwig-Maximilians-University Muenchen, Munich, Germany
| | - Rüdiger Wanke
- Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University Muenchen, Munich, Germany
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17
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Drummond BE, Wingert RA. Insights into kidney stem cell development and regeneration using zebrafish. World J Stem Cells 2016; 8:22-31. [PMID: 26981168 PMCID: PMC4766248 DOI: 10.4252/wjsc.v8.i2.22] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/28/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Kidney disease is an escalating global health problem, for which the formulation of therapeutic approaches using stem cells has received increasing research attention. The complexity of kidney anatomy and function, which includes the diversity of renal cell types, poses formidable challenges in the identification of methods to generate replacement structures. Recent work using the zebrafish has revealed their high capacity to regenerate the integral working units of the kidney, known as nephrons, following acute injury. Here, we discuss these findings and explore the ways that zebrafish can be further utilized to gain a deeper molecular appreciation of renal stem cell biology, which may uncover important clues for regenerative medicine.
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18
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Brown CA, Elliott J, Schmiedt CW, Brown SA. Chronic Kidney Disease in Aged Cats: Clinical Features, Morphology, and Proposed Pathogeneses. Vet Pathol 2016; 53:309-26. [PMID: 26869151 DOI: 10.1177/0300985815622975] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic kidney disease (CKD) is the most common metabolic disease of domesticated cats, with most affected cats being geriatric (>12 years of age). The prevalence of CKD in cats exceeds that observed in dogs, and the frequency of the diagnosis of CKD in cats has increased in recent decades. Typical histologic features include interstitial inflammation, tubular atrophy, and fibrosis with secondary glomerulosclerosis. In contrast to people and dogs, primary glomerulopathies with marked proteinuria are remarkably rare findings in cats. Although a variety of primary renal diseases have been implicated, the disease is idiopathic in most cats. Tubulointerstitial changes, including fibrosis, are present in the early stages of feline CKD and become more severe in advanced disease. A variety of factors-including aging, ischemia, comorbid conditions, phosphorus overload, and routine vaccinations-have been implicated as factors that could contribute to the initiation of this disease in affected cats. Factors that are related to progression of established CKD, which occurs in some but not all cats, include dietary phosphorus intake, magnitude of proteinuria, and anemia. Renal fibrosis, a common histologic feature of aged feline kidneys, interferes with the normal relationship between peritubular capillaries and renal tubules. Experimentally, renal ischemia results in morphologic changes similar to those observed in spontaneous CKD. Renal hypoxia, perhaps episodic, may play a role in the initiation and progression of this disease.
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Affiliation(s)
- C A Brown
- Athens Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - J Elliott
- Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK
| | - C W Schmiedt
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - S A Brown
- Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
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19
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Puelles VG, Cullen-McEwen LA, Taylor GE, Li J, Hughson MD, Kerr PG, Hoy WE, Bertram JF. Human podocyte depletion in association with older age and hypertension. Am J Physiol Renal Physiol 2016; 310:F656-F668. [PMID: 26792066 DOI: 10.1152/ajprenal.00497.2015] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/12/2016] [Indexed: 12/27/2022] Open
Abstract
Podocyte depletion plays a major role in the development and progression of glomerulosclerosis. Many kidney diseases are more common in older age and often coexist with hypertension. We hypothesized that podocyte depletion develops in association with older age and is exacerbated by hypertension. Kidneys from 19 adult Caucasian American males without overt renal disease were collected at autopsy in Mississippi. Demographic data were obtained from medical and autopsy records. Subjects were categorized by age and hypertension as potential independent and additive contributors to podocyte depletion. Design-based stereology was used to estimate individual glomerular volume and total podocyte number per glomerulus, which allowed the calculation of podocyte density (number per volume). Podocyte depletion was defined as a reduction in podocyte number (absolute depletion) or podocyte density (relative depletion). The cortical location of glomeruli (outer or inner cortex) and presence of parietal podocytes were also recorded. Older age was an independent contributor to both absolute and relative podocyte depletion, featuring glomerular hypertrophy, podocyte loss, and thus reduced podocyte density. Hypertension was an independent contributor to relative podocyte depletion by exacerbating glomerular hypertrophy, mostly in glomeruli from the inner cortex. However, hypertension was not associated with podocyte loss. Absolute and relative podocyte depletion were exacerbated by the combination of older age and hypertension. The proportion of glomeruli with parietal podocytes increased with age but not with hypertension alone. These findings demonstrate that older age and hypertension are independent and additive contributors to podocyte depletion in white American men without kidney disease.
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Affiliation(s)
- Victor G Puelles
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia;
| | - Luise A Cullen-McEwen
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Georgina E Taylor
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Jinhua Li
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Michael D Hughson
- Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Peter G Kerr
- Department of Nephrology, Monash Medical Centre, and Department of Medicine, Monash University, Melbourne, Victoria, Australia; and
| | - Wendy E Hoy
- Centre for Chronic Disease, The University of Queensland, Brisbane, Queensland, Australia
| | - John F Bertram
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
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20
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Transgenic Strategies to Study Podocyte Loss and Regeneration. Stem Cells Int 2015; 2015:678347. [PMID: 26089920 PMCID: PMC4451768 DOI: 10.1155/2015/678347] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 03/09/2015] [Accepted: 03/10/2015] [Indexed: 01/22/2023] Open
Abstract
Podocyte death and regeneration are major topics in kidney research but remain controversial. Data obtained in humans demonstrate the existence of cells sited along Bowman's capsule that behave as podocyte progenitors in vitro and in in vivo mouse models of podocyte injury xenotrasplanted with this human-derived population. However, this podocyte reservoir still remains elusive in murine models, where it could be more easily studied. Transgenic models can be a powerful tool to identify this population and to better understand its dynamics and hierarchies in both physiological and pathological conditions. Indeed, exploiting transgenic approaches allows detecting, at the single cell level, movements, cell death, and replacement. Moreover, through lineage tracing it is now possible to identify specific population increase and to point out clonal expansions during or after the regenerative processes. However, applying transgenic strategies to study glomerular regeneration requires the search of markers to unequivocally identify this progenitor population. Achieving this aim would lead to a deep comprehension of the biological processes that underlie glomerular regeneration and clarify how different cell pools interface during this phase. Here we discuss strategies that have been used and new approaches in transgenic models finalized to study podocyte loss and subsequent replacement.
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21
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Putting the glomerulus back together: per aspera ad astra ("a rough road leads to the stars"). Kidney Int 2015; 85:991-8. [PMID: 24786868 DOI: 10.1038/ki.2014.51] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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22
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Hou G, Wu V, Singh G, Holzman LB, Tsui CC. Ret is critical for podocyte survival following glomerular injury in vivo. Am J Physiol Renal Physiol 2015; 308:F774-83. [PMID: 25587123 DOI: 10.1152/ajprenal.00483.2014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 01/06/2015] [Indexed: 12/16/2022] Open
Abstract
Podocyte injury and loss directly cause proteinuria and the progression to glomerulosclerosis. Elucidation of the mechanisms of podocyte survival and recovery from injury is critical for designing strategies to prevent the progression of glomerular diseases. Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated in both nonimmune and immune-mediated in vitro and in vivo models of glomerular diseases. We investigated whether Ret, a known receptor tyrosine kinase critical for kidney morphogenesis and neuronal growth and development, is necessary for glomerular and podocyte development and survival in vivo. Since deletions of both GDNF and Ret result in embryonic lethality due to kidney agenesis, we examined the role of Ret in vivo by generating mice with a conditional deletion of Ret in podocytes (Ret(flox/flox); Nphs2-Cre). In contrast to the lack of any developmental and maintenance deficits, Ret(flox/flox); Nphs2-Cre mice showed a significantly enhanced susceptibility to adriamycin nephropathy, a rodent model of focal segmental glomerulosclerosis. Thus, these findings demonstrated that the Ret signaling pathway is important for podocyte survival and recovery from glomerular injury in vivo.
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Affiliation(s)
- Guoqing Hou
- Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and
| | - Victoria Wu
- Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and
| | - Gulmohar Singh
- Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and
| | - Lawrence B Holzman
- Division of Renal Electrolyte and Hypertension, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Cynthia C Tsui
- Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and
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Xu W, Ge Y, Liu Z, Gong R. Glycogen synthase kinase 3β orchestrates microtubule remodeling in compensatory glomerular adaptation to podocyte depletion. J Biol Chem 2014; 290:1348-63. [PMID: 25468908 DOI: 10.1074/jbc.m114.593830] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Reminiscent of neural repair, following podocyte depletion, remnant-surviving podocytes exhibit a considerable adaptive capacity to expand and cover the denuded renal glomerular basement membrane. Microtubules, one of the principal cytoskeletal components of podocyte major processes, play a crucial role in podocyte morphogenesis and podocyte process outgrowth, branching, and elongation. Here, we demonstrated that the microtubule-associated proteins Tau and collapsin response mediator protein (CRMP) 2, key regulators of microtubule dynamics, were abundantly expressed by glomerular podocytes in vivo and in vitro, interacted with glycogen synthase kinase (GSK)3β, and served as its putative substrates. GSK3β overactivity induced by adriamycin injury or by a constitutively active mutant of GSK3β augmented phosphorylation of Tau and CRMP2, concomitant with microtubule depolymerization, cell body shrinkage, and shortening of podocyte processes. Conversely, inhibition of GSK3β by a dominant negative mutant or by lithium, a Food and Drug Administration-approved neuroprotective mood stabilizer, diminished Tau and CRMP2 phosphorylation, resulting in microtubule polymerization, podocyte expansion, and lengthening of podocyte processes. In a mouse model of adriamycin-induced podocyte depletion and nephropathy, delayed administration of a single low dose of lithium attenuated proteinuria and ameliorated progressive glomerulosclerosis despite no correction of podocytopenia. Mechanistically, lithium therapy obliterated GSK3β overactivity, mitigated phosphorylation of Tau and CRMP2, and enhanced microtubule polymerization and stabilization in glomeruli in adriamycin-injured kidneys, associated with elongation of podocyte major processes. Collectively, our findings suggest that the GSK3β-dictated podocyte microtubule dynamics might serve as a novel therapeutic target to reinforce the compensatory glomerular adaptation to podocyte loss.
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Affiliation(s)
- Weiwei Xu
- From the National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China and the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903
| | - Yan Ge
- the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903
| | - Zhihong Liu
- From the National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China and
| | - Rujun Gong
- the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903
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Venkatachalam MA. Could Autophagic Exhaustion Be a Final Common Pathway for Podocytopathy in FSGS? J Am Soc Nephrol 2014; 26:999-1001. [PMID: 25406340 DOI: 10.1681/asn.2014090919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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26
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Kroeger PT, Wingert RA. Using zebrafish to study podocyte genesis during kidney development and regeneration. Genesis 2014; 52:771-92. [PMID: 24920186 DOI: 10.1002/dvg.22798] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/08/2014] [Accepted: 06/09/2014] [Indexed: 12/21/2022]
Abstract
During development, vertebrates form a progression of up to three different kidneys that are comprised of functional units termed nephrons. Nephron composition is highly conserved across species, and an increasing appreciation of the similarities between zebrafish and mammalian nephron cell types has positioned the zebrafish as a relevant genetic system for nephrogenesis studies. A key component of the nephron blood filter is a specialized epithelial cell known as the podocyte. Podocyte research is of the utmost importance as a vast majority of renal diseases initiate with the dysfunction or loss of podocytes, resulting in a condition known as proteinuria that causes nephron degeneration and eventually leads to kidney failure. Understanding how podocytes develop during organogenesis may elucidate new ways to promote nephron health by stimulating podocyte replacement in kidney disease patients. In this review, we discuss how the zebrafish model can be used to study kidney development, and how zebrafish research has provided new insights into podocyte lineage specification and differentiation. Further, we discuss the recent discovery of podocyte regeneration in adult zebrafish, and explore how continued basic research using zebrafish can provide important knowledge about podocyte genesis in embryonic and adult environments. genesis 52:771-792, 2014. © 2014 Wiley Periodicals, Inc.
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Affiliation(s)
- Paul T Kroeger
- Department of Biological Sciences and Center for Zebrafish Research, University of Notre Dame, Notre Dame, Indiana, 46556
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Wanner N, Hartleben B, Herbach N, Goedel M, Stickel N, Zeiser R, Walz G, Moeller MJ, Grahammer F, Huber TB. Unraveling the role of podocyte turnover in glomerular aging and injury. J Am Soc Nephrol 2014; 25:707-16. [PMID: 24408871 DOI: 10.1681/asn.2013050452] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Podocyte loss is a major determinant of progressive CKD. Although recent studies showed that a subset of parietal epithelial cells can serve as podocyte progenitors, the role of podocyte turnover and regeneration in repair, aging, and nephron loss remains unclear. Here, we combined genetic fate mapping with highly efficient podocyte isolation protocols to precisely quantify podocyte turnover and regeneration. We demonstrate that parietal epithelial cells can give rise to fully differentiated visceral epithelial cells indistinguishable from resident podocytes and that limited podocyte renewal occurs in a diphtheria toxin model of acute podocyte ablation. In contrast, the compensatory programs initiated in response to nephron loss evoke glomerular hypertrophy, but not de novo podocyte generation. In addition, no turnover of podocytes could be detected in aging mice under physiologic conditions. In the absence of podocyte replacement, characteristic features of aging mouse kidneys included progressive accumulation of oxidized proteins, deposits of protein aggregates, loss of podocytes, and glomerulosclerosis. In summary, quantitative investigation of podocyte regeneration in vivo provides novel insights into the mechanism and capacity of podocyte turnover and regeneration in mice. Our data reveal that podocyte generation is mainly confined to glomerular development and may occur after acute glomerular injury, but it fails to regenerate podocytes in aging kidneys or in response to nephron loss.
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Ponticelli C, Graziani G. Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults. Expert Rev Clin Immunol 2013; 9:251-61. [PMID: 23445199 DOI: 10.1586/eci.12.109] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, IRCCS Humanitas Hospital, via Manzoni 56,20089 Rozzano, Milano, Italy.
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Grahammer F, Wanner N, Huber TB. Podocyte regeneration: who can become a podocyte? THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:333-5. [PMID: 23727347 DOI: 10.1016/j.ajpath.2013.04.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 04/18/2013] [Indexed: 11/28/2022]
Abstract
This Commentary highlights the article by Pippin et al that showed that renin lineage cells may enhance glomerular regeneration by serving as progenitors for glomerular epithelial cells in glomerular disease characterized by podocyte depletion.
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Affiliation(s)
- Florian Grahammer
- Renal Division, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany
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Li Y, Wingert RA. Regenerative medicine for the kidney: stem cell prospects & challenges. Clin Transl Med 2013; 2:11. [PMID: 23688352 PMCID: PMC3665577 DOI: 10.1186/2001-1326-2-11] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/14/2013] [Indexed: 12/22/2022] Open
Abstract
The kidney has key roles in maintaining human health. There is an escalating medical crisis in nephrology as growing numbers of patients suffer from kidney diseases that culminate in organ failure. While dialysis and transplantation provide life-saving treatments, these therapies are rife with limitations and place significant burdens on patients and healthcare systems. It has become imperative to find alternative ways to treat existing kidney conditions and preemptive means to stave off renal dysfunction. The creation of innovative medical approaches that utilize stem cells has received growing research attention. In this review, we discuss the regenerative and maladaptive cellular responses that occur during acute and chronic kidney disease, the emerging evidence about renal stem cells, and some of the issues that lie ahead in bridging the gap between basic stem cell biology and regenerative medicine for the kidney.
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Affiliation(s)
- Yue Li
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
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