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1
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Wang M, Yang J, Fang X, Lin W, Yang Y. Membranous nephropathy: pathogenesis and treatments. MedComm (Beijing) 2024; 5:e614. [PMID: 38948114 PMCID: PMC11214595 DOI: 10.1002/mco2.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 07/02/2024] Open
Abstract
Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end-stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.
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Affiliation(s)
- Mengqiong Wang
- Department of NephrologyCenter for Regeneration and Aging MedicineThe Fourth Affiliated Hospital of School of Medicineand International School of Medicine, International Institutes of MedicineZhejiang UniversityYiwuChina
| | - Jingjuan Yang
- Department of NephrologyCenter for Regeneration and Aging MedicineThe Fourth Affiliated Hospital of School of Medicineand International School of Medicine, International Institutes of MedicineZhejiang UniversityYiwuChina
| | - Xin Fang
- Department of NephrologyCenter for Regeneration and Aging MedicineThe Fourth Affiliated Hospital of School of Medicineand International School of Medicine, International Institutes of MedicineZhejiang UniversityYiwuChina
| | - Weiqiang Lin
- Department of NephrologyCenter for Regeneration and Aging MedicineThe Fourth Affiliated Hospital of School of Medicineand International School of Medicine, International Institutes of MedicineZhejiang UniversityYiwuChina
| | - Yi Yang
- Department of NephrologyCenter for Regeneration and Aging MedicineThe Fourth Affiliated Hospital of School of Medicineand International School of Medicine, International Institutes of MedicineZhejiang UniversityYiwuChina
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Maglica M, Kelam N, Perutina I, Racetin A, Rizikalo A, Filipović N, Kuzmić Prusac I, Mišković J, Vukojević K. Immunoexpression Pattern of Autophagy-Related Proteins in Human Congenital Anomalies of the Kidney and Urinary Tract. Int J Mol Sci 2024; 25:6829. [PMID: 38999938 PMCID: PMC11241479 DOI: 10.3390/ijms25136829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
The purpose of this study was to evaluate the spatiotemporal immunoexpression pattern of microtubule-associated protein 1 light chain 3 beta (LC3B), glucose-regulated protein 78 (GRP78), heat shock protein 70 (HSP70), and lysosomal-associated membrane protein 2A (LAMP2A) in normal human fetal kidney development (CTRL) and kidneys affected with congenital anomalies of the kidney and urinary tract (CAKUT). Human fetal kidneys (control, horseshoe, dysplastic, duplex, and hypoplastic) from the 18th to the 38th developmental week underwent epifluorescence microscopy analysis after being stained with antibodies. Immunoreactivity was quantified in various kidney structures, and expression dynamics were examined using linear and nonlinear regression modeling. The punctate expression of LC3B was observed mainly in tubules and glomerular cells, with dysplastic kidneys displaying distinct staining patterns. In the control group's glomeruli, LAMP2A showed a sporadic, punctate signal; in contrast to other phenotypes, duplex kidneys showed significantly stronger expression in convoluted tubules. GRP78 had a weaker expression in CAKUT kidneys, especially hypoplastic ones, while normal kidneys exhibited punctate staining of convoluted tubules and glomeruli. HSP70 staining varied among phenotypes, with dysplastic and hypoplastic kidneys exhibiting stronger staining compared to controls. Expression dynamics varied among observed autophagy markers and phenotypes, indicating their potential roles in normal and dysfunctional kidney development.
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Affiliation(s)
- Mirko Maglica
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ilija Perutina
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Azer Rizikalo
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Natalija Filipović
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ivana Kuzmić Prusac
- Department of Pathology, University Hospital Center Split, 21000 Split, Croatia
| | - Josip Mišković
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Katarina Vukojević
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
- Center for Translational Research in Biomedicine, School of Medicine, University of Split, 21000 Split, Croatia
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3
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Wan Q, Zhou J, Wu Y, Shi L, Liu W, Ou J, Gao J. TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy. Ren Fail 2022; 44:1216-1226. [PMID: 35837694 PMCID: PMC9291659 DOI: 10.1080/0886022x.2022.2079527] [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] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis. METHODS Forty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks. RESULTS BSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice. CONCLUSION TNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.
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Affiliation(s)
- Qiang Wan
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.,Department of Nephrology, Beilun Traditional Chinese Medicine Hospital, Ningbo, China
| | - Jiabao Zhou
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yansheng Wu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Liqiang Shi
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Weiwei Liu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Jiaoying Ou
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.,Preventive treatment of disease center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiandong Gao
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease, Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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Cao Y, Lin JH, Hammes HP, Zhang C. Cellular phenotypic transitions in diabetic nephropathy: An update. Front Pharmacol 2022; 13:1038073. [PMID: 36408221 PMCID: PMC9666367 DOI: 10.3389/fphar.2022.1038073] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022] Open
Abstract
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.
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Affiliation(s)
- Yiling Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji-Hong Lin
- 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Hans-Peter Hammes
- 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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5
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Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis. Int J Mol Sci 2021; 22:ijms222111857. [PMID: 34769288 PMCID: PMC8584225 DOI: 10.3390/ijms222111857] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/08/2021] [Accepted: 10/30/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.
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Liu W, Shi L, Wan Q, Wu Y, Huang D, Ou J, Liu Q, Guan X, Yang Y, Zhang X, Gao J. Huangqi Guizhi Wuwu Decoction attenuates Podocyte cytoskeletal protein damage in IgA nephropathy rats by regulating AT1R/Nephrin/c-Abl pathway. Biomed Pharmacother 2021; 142:111907. [PMID: 34339916 DOI: 10.1016/j.biopha.2021.111907] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 01/17/2023] Open
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqi Guizhi Wuwu Decoction(HQGZWWD) is a Traditional Chinese Medicine formula from Synopsis of Golden Chamber used to treat blood arthralgia. According to the principle that the same treatment can be used for different diseases, HQGZWWD has proven effective for IgA nephropathy (IgAN) associated with spleen and kidney yang deficiency. AIM OF THE STUDY In this study, we investigated the mechanism by which HQGZWWD alleviates proteinuria and protects renal function in rats with IgAN by regulating the AT1R/Nephrin/c-Abl pathway. METHODS Rats were randomly divided into six groups: control, IgAN model, IgAN model treated with low-dose HQGZWWD, IgAN model treated with medium-dose HQGZWWD, IgAN model treated with high-dose HQGZWWD, and IgAN model treated with valsartan. IgAN was induced using bovine γ-globulin. We evaluated the mediating effects of HQGZWWD on podocyte cytoskeletal proteins, the AT1R/Nephrin/c-Abl pathway, upstream tumor necrosis factor-α (TNF-α), and TNF-α receptor-1 (TNFR1). RESULTS The IgAN rats displayed proteinuria, IgA deposition in the mesangial region, and podocyte cytoskeletal protein damage. The expression of TNF-α, TNFR1, AT1R, and c-Abl was increased in the IgAN rat kidney, whereas the expression of nephrin, podocin, ACTN4, and phosphorylated nephrin (p-nephrin) was reduced. HQGZWWD treatment significantly alleviated podocyte cytoskeletal protein damage in the IgAN rats, upregulated the expression of nephrin, podocin, and ACTN4, and the colocalized expression of F-actin and nephrin. This study demonstrates that HQGZWWD attenuates podocyte cytoskeletal protein damage by regulating the AT1R-nephrin- c-Abl pathway, upregulating the expression of p-nephrin, and downregulating the expression of AT1R and c-Abl. CONCLUSIONS These results indicate that HQGZWWD attenuates podocyte cytoskeletal protein damage in IgAN rats by regulating the AT1R/Nephrin/c-Abl pathway, providing a potential therapeutic approach for IgAN.
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MESH Headings
- Actinin/genetics
- Actinin/metabolism
- Actins/metabolism
- Animals
- Cytoskeletal Proteins/metabolism
- Disease Models, Animal
- Down-Regulation/drug effects
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Glomerulonephritis, IGA/drug therapy
- Glomerulonephritis, IGA/metabolism
- Glomerulonephritis, IGA/pathology
- Glomerulonephritis, IGA/physiopathology
- Immunoglobulin A/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Podocytes/drug effects
- Protective Agents/chemistry
- Protective Agents/pharmacology
- Protective Agents/therapeutic use
- Proteinuria/metabolism
- Proto-Oncogene Proteins c-abl/metabolism
- Rats, Sprague-Dawley
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Signal Transduction/drug effects
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
- Rats
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Affiliation(s)
- Weiwei Liu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Liqiang Shi
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Qiang Wan
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Yansheng Wu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Di Huang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Jiaoying Ou
- Department of Internal Medicine, Shanghai TCM-Integrated Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, No. 184 Road Baoding, Shanghai 200082, China
| | - Qiuyu Liu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Xin Guan
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Yuzhu Yang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Xiaotian Zhang
- Preventive treatment of disease center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Shanghai 201203, China
| | - Jiandong Gao
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, No. 528 Zhangheng Road, Shanghai 201203, China.
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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8
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Rinschen MM, Gödel M, Grahammer F, Zschiedrich S, Helmstädter M, Kretz O, Zarei M, Braun DA, Dittrich S, Pahmeyer C, Schroder P, Teetzen C, Gee H, Daouk G, Pohl M, Kuhn E, Schermer B, Küttner V, Boerries M, Busch H, Schiffer M, Bergmann C, Krüger M, Hildebrandt F, Dengjel J, Benzing T, Huber TB. A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes. Cell Rep 2019; 23:2495-2508. [PMID: 29791858 PMCID: PMC5986710 DOI: 10.1016/j.celrep.2018.04.059] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 02/07/2018] [Accepted: 04/15/2018] [Indexed: 12/31/2022] Open
Abstract
Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease.
Deep proteome and transcriptome analyses of native podocytes unravel druggable targets Static and dynamic proteomics uncover features of podocyte identity and proteostasis Candidate genes for nephrotic syndrome were predicted based on multi-omic integration FARP1 is a previously unreported candidate gene for human proteinuric kidney disease
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Affiliation(s)
- Markus M Rinschen
- Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany.
| | - Markus Gödel
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Florian Grahammer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Stefan Zschiedrich
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Martin Helmstädter
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Oliver Kretz
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Mostafa Zarei
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany
| | - Daniela A Braun
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Sebastian Dittrich
- Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Caroline Pahmeyer
- Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Patricia Schroder
- Department of Medicine/Nephrology, Hannover Medical School, 30625 Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04609, USA
| | - Carolin Teetzen
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - HeonYung Gee
- Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04609, USA; Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Ghaleb Daouk
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Elisa Kuhn
- Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany
| | - Bernhard Schermer
- Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany
| | - Victoria Küttner
- Department for Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Department of Dermatology, Medical Center - University of Freiburg, 79106 Freiburg, Germany
| | - Melanie Boerries
- Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), 79106 Freiburg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Hauke Busch
- Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany; Lübeck Institute for Experimental Dermatology (LIED), University of Lübeck, 23562 Lübeck, Germany
| | - Mario Schiffer
- Department of Medicine/Nephrology, Hannover Medical School, 30625 Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04609, USA
| | - Carsten Bergmann
- Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany
| | - Marcus Krüger
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Friedhelm Hildebrandt
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joern Dengjel
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany; Department of Dermatology, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland; BIOSS Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany
| | - Thomas Benzing
- Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany.
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.
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9
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Zhu Y, Li Q, Xun W, Chen Y, Zhang C, Sun S. Blocking P2X7 receptor ameliorates oxidized LDL-mediated podocyte apoptosis. Mol Biol Rep 2019; 46:3809-3816. [DOI: 10.1007/s11033-019-04823-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/13/2019] [Indexed: 01/21/2023]
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10
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A Glucose-Dependent Pharmacokinetic/ Pharmacodynamic Model of ACE Inhibition in Kidney Cells. Processes (Basel) 2019. [DOI: 10.3390/pr7030131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of renal failure. Podocytes are terminally differentiated renal epithelial cells that are key targets of damage due to DKD. Podocytes express a glucose-stimulated local renin-angiotensin system (RAS) that produces angiotensin II (ANG II). Local RAS differs from systemic RAS, which has been studied widely. Hyperglycemia increases the production of ANG II by podocyte cells, leading to podocyte injury. Angiotensin-converting enzyme (ACE) is involved in the production of ANG II, and ACE inhibitors are drugs used to suppress elevated ANG II concentration. As systemic RAS differs from the local RAS in podocytes, ACE inhibitor drugs should act differently in local versus systemic contexts. Experimental and computational studies have considered the pharmacokinetics (PK) and pharmacodynamics (PD) of ACE inhibition of the systemic RAS. Here, a PK/PD model for ACE inhibition is developed for the local RAS in podocytes. The model takes constant or dynamic subject-specific glucose concentration input to predict the ANG II concentration and the corresponding effects of drug doses locally and systemically. The model is developed for normal and impaired renal function in combination with different glucose conditions, thus enabling the study of various pathophysiological conditions. Parameter uncertainty is also analyzed. Such a model can improve the study of the effects of drugs at the cellular level and can aid in development of therapeutic approaches to slow the progression of DKD.
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11
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He C, Shi W, Li R, Zhang L. [NFAT2 mediates high glucose-induced apoptosis in glomerular podocytes in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2018; 38:1270-1276. [PMID: 30377135 DOI: 10.3969/j.issn.1673-4254.2018.10.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To determine whether hyperglycemia activates NFAT2 in cultured podocytes to cause podocyte apoptosis and explore the role of NFAT2 in high glucose-induced podocyte apoptosis. METHODS Immortalized mouse podocytes were cultured in the presence of normal (5.3 mmol/L) or high glucose (10, 20, 30, and 40 mmol/L) or pretreated with 11R-vivit (100 nmol/L) or cyclosporine A (500 nmol/L) before exposure to 20 mmol/L glucose for different durations (0.5-48 h). The activation of NFAT2 in the podocytes was detected using Western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia-induced podocyte apoptosis was explored by observing the inhibition of NFAT2 activation by 11R-vivit using flow cytometry. Intracellular Ca2+ was monitored in high glucose-treated podocytes using Fluo-3/AM. The mRNA and protein expressions of the apoptosis gene Bax were detected using real time-qPCR and Western blotting. RESULTS Exposure to high glucose in the medium time- and dose-dependently activated NFAT2 in cultured podocytes. Pretreatment with cyclosporine A or 11R- VIVIT completely blocked nuclear accumulation of NFAT2. Treatment with 11R- vivit also inhibited high glucoseinduced apoptosis in cultured podocytes. Exposure to high glucose obviously increased [Ca2 +]I in the podocytes to cause activation of calcineurin and the subsequent increment of nuclear accumulation of NFAT2 and Bax expression. CONCLUSIONS High glucose-induced apoptosis in podocytes is mediated by calcineurin/NFAT2/Bax signaling pathway, which may serve as a potential target for therapeutic intervention.
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Affiliation(s)
- Chaosheng He
- Department of Nephrology, Guangdong General Hospital//Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Wei Shi
- Department of Nephrology, Guangdong General Hospital//Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Ruizhao Li
- Department of Nephrology, Guangdong General Hospital//Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Li Zhang
- Department of Nephrology, Guangdong General Hospital//Guangdong Academy of Medical Sciences, Guangzhou 510080, China
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12
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Mathematical Model for Glucose Dependence of the Local Renin-Angiotensin System in Podocytes. Bull Math Biol 2018. [PMID: 29520569 DOI: 10.1007/s11538-018-0408-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Diabetic kidney disease (DKD) is the primary cause of kidney failure. Diabetic hyperglycemia primarily damages podocyte cells. Podocytes express a local renin-angiotensin system (RAS) that produces angiotensin II (ANG II). ANG II levels are elevated by hyperglycemia, triggering podocyte injury. Quantitative descriptions of glucose dose dependency of ANG II are scarce in the literature. For better understanding of the mechanism of glycemic injury in DKD, a mathematical model is developed to describe the glucose-stimulated local RAS in podocytes. The model of the RAS signaling pathway in podocytes tracks peptides and enzymes without explicit glucose dependence. Local and global sensitivity analyses are used to identify the key parameters to be estimated in the model. Three approaches are explored to incorporate glucose dependency through linear ramp functions for the sensitive parameters. The first approach uses inferences from literature data to estimate the parameter values, while the other approaches reduce the number of assumptions by using least-squares regression to estimate all or a subset of the parameters. Physiological parameter values and RAS peptide concentrations ranges are used to discriminate between plausible models for the glucose dose dependency. This is the first model of the theory of the local RAS mechanism specific to podocyte cells to track ANG II levels in a range of glycemic conditions that may contribute to podocyte damage in DKD. The ability to track ANG II behavior could enable prediction of its downstream effects on podocytes and provide opportunities to better characterize pathophysiological features of DKD progression.
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13
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Abstract
Podocytes exhibit a unique cytoskeletal architecture that is fundamentally linked to their function in maintaining the kidney filtration barrier. The cytoskeleton regulates podocyte shape, structure, stability, slit diaphragm insertion, adhesion, plasticity, and dynamic response to environmental stimuli. Genetic mutations demonstrate that even slight impairment of the podocyte cytoskeletal apparatus results in proteinuria and glomerular disease. Moreover, mechanisms underpinning all acquired glomerular pathologies converge on disruption of the cytoskeleton, suggesting that this subcellular structure could be targeted for therapeutic purposes. This review summarizes our current understanding of the function of the cytoskeleton in podocytes and the associated implications for pathophysiology.
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Affiliation(s)
- Christoph Schell
- Institute of Surgical Pathology and.,Department of Medicine IV, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Tobias B Huber
- Department of Medicine IV, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; .,III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.,BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University, Freiburg, Germany
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14
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Udagawa T, Jo T, Yanagihara T, Shimizu A, Mitsui J, Tsuji S, Morishita S, Onai R, Miura K, Kanda S, Kajiho Y, Tsurumi H, Oka A, Hattori M, Harita Y. Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. Pediatr Nephrol 2017; 32:801-809. [PMID: 27942854 DOI: 10.1007/s00467-016-3549-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 11/02/2016] [Accepted: 11/08/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disorder for which more than 25 single-gene hereditary causes have been identified. METHODS Whole exome sequencing was performed in a 3-year-old girl with SRNS. We analyzed the expression of Crb2 and slit diaphragm molecules in the patient's glomeruli, and compared it with that of controls or other nephrotic patients. RESULTS Whole-exome analysis identified novel compound heterozygous mutations in exons 10 and 12 of CRB2 (p.Trp1086ArgfsX64 and p.Asn1184Thr, each from different parents; Asn1184 within extracellular 15th EGF repeat domain). Renal pathology showed focal segmental glomerulosclerosis with effaced podocyte foot processes in a small area, with significantly decreased Crb2 expression. Molecules critical for slit diaphragm were well-expressed in this patient's podocytes. Crb2 expression was not altered in the other patients with congenital nephrotic syndrome with NPHS1 mutations. CONCLUSIONS These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant NS. Although CRB2 mutations previously found in SRNS patients have been clustered within the extracellular tenth EGF-like domain of this protein, the present results expand the variation of CRB2 mutations that cause SRNS.
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Affiliation(s)
- Tomohiro Udagawa
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tohaku Jo
- Department of Pediatrics, Nippon Medical School, Tokyo, Japan
| | | | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Jun Mitsui
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shoji Tsuji
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shinichi Morishita
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Reiko Onai
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kenichiro Miura
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shoichiro Kanda
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yuko Kajiho
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Haruko Tsurumi
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Akira Oka
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Sinjuku-ku, Tokyo, Japan
| | - Yutaka Harita
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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15
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Fujino T, Hasebe N. Alteration of histone H3K4 methylation in glomerular podocytes associated with proteinuria in patients with membranous nephropathy. BMC Nephrol 2016; 17:179. [PMID: 27855638 PMCID: PMC5114780 DOI: 10.1186/s12882-016-0390-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 11/03/2016] [Indexed: 01/06/2023] Open
Abstract
Background Histone H3K4 trimethylation (H3K4 me3) is found in active euchromatic regions and plays an important role in podocyte function in which actin filaments are abundant in the foot processes. The pathogenesis of membranous nephropathy (MN), the most prevalent cause of primary nephrotic syndrome in the middle-aged and elderly, is podocyte dysfunction. Methods We investigated the role of H3K4 me3 in podocyte dysfunction in nephrotic syndrome using cultured podocytes and a mouse proteinuria model induced by LPS. We examined renal biopsy specimens from six patients with nephrotic syndrome caused by Phospholipase-A2-Receptor-positive primary MN. Results H3K4 me3 exhibited a pattern of nuclear expression in podocytes of the kidneys from patients with MN. The overlapping expression of H3K4 me3 and cathepsin L (a potent endoprotease causing the breakdown of actin-associated protein within lysosomal compartments in kidney podocytes) were higher in patients with MN compared with the controls. Histone H3K4 me3 in kidney podocytes was negatively correlated with synaptopodin, an actin-associated protein in podocytes, and the expression was positively correlated with the proteinuria levels in patients with MN. Histone H3K4 me3 levels were elevated in podocytes of LPS-treated mice, combined with an increase in podocyte swelling, an elevation of serum creatinine and urine albumin, increased cathepsin L, and decreased synaptopodin expression. Histone H3K4 me3 levels at the cathepsin L promoter were elevated in LPS-exposed mouse kidneys. The administration of shRNA against MLL3 (an H3K4 methyltransferase) to LPS-treated mice and cultured podocytes co-cultured with LPS-stimulated macrophages ameliorated podocyte swelling, an elevation in the serum creatinine and urine albumin levels and an increased expression of histone H3K4 me3 and cathepsin L, and a decreased expression of synaptopodin and increase in histone H3K4 me3 levels at the cathepsin L promoter. Conclusions Histone H3K4 me3 upregulation may be involved in podocyte dysfunction and the pathophysiology of MN. Targeting this epigenetic signature of histone H3K4 me3 followed by modulating the actin dynamics may be an effective strategy to ameliorate the consequences of MN.
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Affiliation(s)
- Takayuki Fujino
- Department of Internal Medicine, Cardiovascular Respiratory and Neurology and Nephrology Division, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
| | - Naoyuki Hasebe
- Department of Internal Medicine, Cardiovascular Respiratory and Neurology and Nephrology Division, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
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16
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Zhang L, Ren Z, Yang Q, Ding G. Csk regulates angiotensin II-induced podocyte apoptosis. Apoptosis 2016; 21:846-55. [DOI: 10.1007/s10495-016-1256-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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17
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Abstract
Endothelin-1 (ET-1) is a 21-amino acid peptide with mitogenic and powerful vasoconstricting properties. Under healthy conditions, ET-1 is expressed constitutively in all cells of the glomerulus and participates in homeostasis of glomerular structure and filtration function. Under disease conditions, increases in ET-1 are critically involved in initiating and maintaining glomerular inflammation, glomerular basement membrane hypertrophy, and injury of podocytes (visceral epithelial cells), thereby promoting proteinuria and glomerulosclerosis. Here, we review the role of ET-1 in the function of glomerular endothelial cells, visceral (podocytes) and parietal epithelial cells, mesangial cells, the glomerular basement membrane, stromal cells, inflammatory cells, and mesenchymal stem cells. We also discuss molecular mechanisms by which ET-1, predominantly through activation of the ETA receptor, contributes to injury to glomerular cells, and review preclinical and clinical evidence supporting its pathogenic role in glomerular injury in chronic renal disease. Finally, the therapeutic rationale for endothelin antagonists as a new class of antiproteinuric drugs is discussed.
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Affiliation(s)
- Matthias Barton
- Molecular Internal Medicine, University of Zurich, Zurich, Switzerland.
| | - Andrey Sorokin
- Department of Medicine, Kidney Disease Center, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI
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18
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Abstract
Podocytes are highly specialized cells of the kidney glomerulus that wrap around capillaries and that neighbor cells of the Bowman’s capsule. When it comes to glomerular filtration, podocytes play an active role in preventing plasma proteins from entering the urinary ultrafiltrate by providing a barrier comprising filtration slits between foot processes, which in aggregate represent a dynamic network of cellular extensions. Foot processes interdigitate with foot processes from adjacent podocytes and form a network of narrow and rather uniform gaps. The fenestrated endothelial cells retain blood cells but permit passage of small solutes and an overlying basement membrane less permeable to macromolecules, in particular to albumin. The cytoskeletal dynamics and structural plasticity of podocytes as well as the signaling between each of these distinct layers are essential for an efficient glomerular filtration and thus for proper renal function. The genetic or acquired impairment of podocytes may lead to foot process effacement (podocyte fusion or retraction), a morphological hallmark of proteinuric renal diseases. Here, we briefly discuss aspects of a contemporary view of podocytes in glomerular filtration, the patterns of structural changes in podocytes associated with common glomerular diseases, and the current state of basic and clinical research.
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Affiliation(s)
- Jochen Reiser
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Mehmet M Altintas
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
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19
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Wu J, Zheng C, Wang X, Yun S, Zhao Y, Liu L, Lu Y, Ye Y, Zhu X, Zhang C, Shi S, Liu Z. MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes. J Clin Invest 2015; 125:4091-106. [PMID: 26436650 DOI: 10.1172/jci81061] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 08/27/2015] [Indexed: 12/21/2022] Open
Abstract
Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are the targets of the microRNA-30 family (miR-30s). We found that these 5 genes are highly expressed as mRNA, but the level of the proteins is low in normal podocytes. Conversely, protein levels were markedly elevated in podocytes from rats treated with puromycin aminonucleoside (PAN) and from patients with focal segmental glomerulosclerosis (FSGS). In both FSGS patients and PAN-treated rats, miR-30s were downregulated in podocytes. In cultured podocytes, PAN or a miR-30 sponge increased TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 expression; calcium influx; intracellular Ca2+ concentration; and calcineurin activity. Moreover, NFATC3 nuclear translocation, synaptopodin degradation, integrin β3 (ITGB3) activation, and actin fiber loss, which are downstream of calcium/calcineurin signaling, were induced by miR-30 reduction but blocked by the calcineurin inhibitor FK506. Podocyte-specific expression of the miR-30 sponge in mice increased calcium/calcineurin pathway component protein expression and calcineurin activity. The mice developed podocyte foot process effacement and proteinuria, which were prevented by FK506. miR-30s also regulated calcium/calcineurin signaling in cardiomyocytes. Together, our results identify miR-30s as essential regulators of calcium/calcineurin signaling.
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20
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Na J, Sweetwyne MT, Park ASD, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell Rep 2015; 12:636-47. [PMID: 26190114 DOI: 10.1016/j.celrep.2015.06.056] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 05/15/2015] [Accepted: 06/17/2015] [Indexed: 01/15/2023] Open
Abstract
Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns. Reducing OGT through genetic or drug means is sufficient to rescue loss of Sns, leading to overall extension of lifespan. We demonstrate upregulation of the Knot ortholog EBF2 in glomeruli of human diabetic nephropathy patients and a mouse ob/ob diabetes model. Furthermore, we demonstrate rescue of Nephrin expression and cell viability in ebf2(-/-) primary podocytes cultured in high glucose.
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Affiliation(s)
- Jianbo Na
- Department of Developmental and Regenerative Biology and School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA
| | - Mariya T Sweetwyne
- Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA
| | - Ae Seo Deok Park
- Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA
| | - Katalin Susztak
- Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA
| | - Ross L Cagan
- Department of Developmental and Regenerative Biology and School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA.
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21
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Ikonomov OC, Sbrissa D, Venkatareddy M, Tisdale E, Garg P, Shisheva A. Class III PI 3-kinase is the main source of PtdIns3P substrate and membrane recruitment signal for PIKfyve constitutive function in podocyte endomembrane homeostasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:1240-50. [PMID: 25619930 DOI: 10.1016/j.bbamcr.2015.01.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/22/2014] [Accepted: 01/16/2015] [Indexed: 11/19/2022]
Abstract
The evolutionarily conserved PIKfyve, which synthesizes PtdIns5P from PtdIns, and PtdIns(3,5)P2 from PtdIns3P, requires PtdIns3P as both an enzyme substrate and a membrane recruitment signal. Whereas the PtdIns3P source is undetermined, class III PI3K (Vps34), the only evolutionarily conserved of the eight mammalian PI3Ks, is presumed as a main candidate. A hallmark of PIKfyve deficiency is formation of multiple translucent cytoplasmic vacuoles seen by light microscopy in cells cultured in complete media. Such an aberrant phenotype is often observed in cells from conditional Vps34 knockout (KO) mice. To clarify the mechanism of Vps34 KO-triggered vacuolation and the PtdIns3P source for PIKfyve functionality, here we have characterized a podocyte cell type derived from Vps34fl/fl mice, which, upon Cre-mediated gene KO, robustly formed cytoplasmic vacuoles resembling those in PikfyveKO MEFs. Vps34wt, expressed in Vps34KO podocytes restored the normal morphology, but only if the endogenous PIKfyve activity was intact. Conversely, expressed PIKfyvewt rescued completely the vacuolation only in PikfyveKO MEFs but not in Vps34KO podocytes. Analyses of phosphoinositide profiles by HPLC and localization patterns by a PtdIns3P biosensor revealed that Vps34 is the main supplier of localized PtdIns3P not only for PIKfyve activity but also for membrane recruitment. Concordantly, Vps34KO podocytes had severely reduced steady-state levels of both PtdIns(3,5)P2 and PtdIns5P, along with PtdIns3P. We further revealed a plausible physiologically-relevant Vps34-independent PtdIns3P supply for PIKfyve, operating through activated class I PI3Ks. Our data provide the first evidence that the vacuolation phenotype in Vps34KO podocytes is due to PIKfyve dysfunction and that Vps34 is a main PtdIns3P source for constitutive PIKfyve functionality.
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Affiliation(s)
- Ognian C Ikonomov
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Diego Sbrissa
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | | | - Ellen Tisdale
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Puneet Garg
- Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Assia Shisheva
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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22
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Cheng YC, Chang JM, Chen CA, Chen HC. Autophagy modulates endoplasmic reticulum stress-induced cell death in podocytes: a protective role. Exp Biol Med (Maywood) 2014; 240:467-76. [PMID: 25322957 DOI: 10.1177/1535370214553772] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 08/04/2014] [Indexed: 01/13/2023] Open
Abstract
Endoplasmic reticulum stress occurs in a variety of patho-physiological mechanisms and there has been great interest in managing this pathway for the treatment of clinical diseases. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In this study, podocytes were exposed to tunicamycin and thapsigargin to induce endoplasmic reticulum stress. Thapsigargin/tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansylcadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on endoplasmic reticulum stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic reticulum stress-induced cell death was decreased at 6 h, but was not reduced at 24 h after Rap+TG or Rap+TM treatment. In contrast, endoplasmic reticulum stress-induced cell death increased at 6 and 24 h after 3-MA+TG or 3-MA+TM treatment. Our study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. In summary, autophagy helps the podocytes from cell death and may contribute to sustain the longevity as a highly differentiated cell lineage.
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Affiliation(s)
- Yu-Chi Cheng
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jer-Ming Chang
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 80708, Taiwan Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chien-An Chen
- Division of Nephrology, Tainan Sinlau Hospital, Tainan 70142, Taiwan
| | - Hung-Chun Chen
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Wang H, Misaki T, Taupin V, Eguchi A, Ghosh P, Farquhar MG. GIV/girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin. J Am Soc Nephrol 2014; 26:314-27. [PMID: 25012178 DOI: 10.1681/asn.2013090985] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα-interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.
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Affiliation(s)
- Honghui Wang
- Departments of Cellular and Molecular Medicine and
| | - Taro Misaki
- Departments of Cellular and Molecular Medicine and
| | | | - Akiko Eguchi
- Medicine, University of California, San Diego, La Jolla, California
| | - Pradipta Ghosh
- Medicine, University of California, San Diego, La Jolla, California
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Schlondorff J. How many Achilles' heels does a podocyte have? An update on podocyte biology: Table 1. Nephrol Dial Transplant 2014; 30:1091-7. [DOI: 10.1093/ndt/gfu214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 05/07/2014] [Indexed: 11/15/2022] Open
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25
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Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest 2014; 124:2333-40. [PMID: 24892707 DOI: 10.1172/jci72271] [Citation(s) in RCA: 649] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. DKD is a prototypical disease of gene and environmental interactions. Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. Blood pressure control, especially with medications that inhibit the angiotensin system, is the only effective way to slow disease progression. While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. Concerted clinical and basic research efforts will be needed to understand DKD pathogenesis and to identify novel drug targets.
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Abstract
In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the pathogenesis of proteinuric kidney disease, has substantially increased. Landmark genetic studies identified mutations in genes expressed by podocytes as a cause of albuminuria and nephrotic syndrome, leading to breakthrough discoveries from many laboratories. These discoveries contributed to a dramatic change in our view of the glomerular filtration barrier of the kidney and of the role of podocyte injury in the development of albuminuria and progressive kidney disease. In the past several years, studies have demonstrated that podocyte injury is a major cause of marked albuminuria and nephrotic syndrome, and have confirmed that podocytes are important for the maintenance of an intact glomerular filtration barrier. An essential role of loss of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease has also been identified. In this Review, we discuss the importance of podocytes for the maintenance of an intact glomerular filtration barrier and their role in albumin handling.
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Affiliation(s)
- Paul Thomas Brinkkoetter
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany
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Madeo J, Zubair A, Marianne F. A review on the role of quinones in renal disorders. SPRINGERPLUS 2013; 2:139. [PMID: 23577302 PMCID: PMC3618882 DOI: 10.1186/2193-1801-2-139] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 03/10/2013] [Indexed: 12/12/2022]
Abstract
Quinones are electron and proton carriers that play a primary role in the aerobic metabolism of virtually every cell in nature. Most physiological quinones are benzoquinones. They undergo highly regulated redox reactions in the mitochondria, Golgi apparatus, plasma membrane and endoplasmic reticulum. Important consequences of these electron transfer reactions are the production of and protection against reactive oxygen species (ROS). Quinones have been extensively studied for both their cytotoxic as well as cellular protective properties and they have been particularly useful in rational drug design. The role of quinones in medicine is explored in this literature review with a particular focus on renal diseases. Due to their high basal metabolism and detoxification role, the kidneys are particularly sensitive to oxidative stress. Regardless of the underlying etiology, ROS plays an important role in both acute kidney injury (AKI) and chronic kidney diseases (CKD). Depending on the oxidative state of the kidney, quinones can be nephrotoxoic or nephro-protective. Many factors play a role in the interaction between quinones and the kidney and the consequences of this are just beginning to be explored.
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Affiliation(s)
- Jennifer Madeo
- Department of Medicine, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554 USA
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Li R, Zhang L, Shi W, Zhang B, Liang X, Liu S, Wang W. NFAT2 mediates high glucose-induced glomerular podocyte apoptosis through increased Bax expression. Exp Cell Res 2013; 319:992-1000. [PMID: 23340267 DOI: 10.1016/j.yexcr.2013.01.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 12/25/2012] [Accepted: 01/07/2013] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hyperglycemia promotes podocyte apoptosis and plays a key role in the pathogenesis of diabetic nephropathy. However, the mechanisms that mediate hyperglycemia-induced podocyte apoptosis is still far from being fully understood. Recent studies reported that high glucose activate nuclear factor of activated T cells (NFAT) in vascular smooth muscle or pancreatic β-cells. Here, we sought to determine if hyperglycemia activates NFAT2 in cultured podocyte and whether this leads to podocyte apoptosis. Meanwhile, we also further explore the mechanisms of NFAT2 activation and NFAT2 mediates high glucose-induced podocyte apoptosis. METHODS Immortalized mouse podocytes were cultured in media containing normal glucose (NG), or high glucose (HG) or HG plus cyclosporine A (a pharmacological inhibitor of calcinerin) or 11R-VIVIT (a special inhibitor of NFAT2). The activation of NFAT2 in podocytes was detected by western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia-induced podocyte apoptosis was further evaluated by observing the inhibition of NFAT2 activation by 11R-VIVIT using flow cytometer. Intracellular Ca(2+) was monitored in HG-treated podcocytes using Fluo-3/AM. The mRNA and protein expression of apoptosis gene Bax were measured by real time-qPCR and western blotting. RESULTS HG stimulation activated NFAT2 in a time- and dose-dependent manner in cultured podocytes. Pretreatment with cyclosporine A (500nM) or 11R-VIVIT (100nM) completely blocked NFAT2 nuclear accumulation. Meanwhile, the apoptosis effects induced by HG were also abrogated by concomitant treatment with 11R-VIVIT in cultured podocytes. We further found that HG also increased [Ca(2+)]i, leading to activation of calcineurin, and subsequent increased nuclear accumulation of NFAT2 and Bax expression in cultured podocytes. CONCLUSION Our results identify a new finding that HG-induced podocyte apoptosis is mediated by calcineurin/NFAT2/Bax signaling pathway, which may present a promising target for therapeutic intervention.
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Affiliation(s)
- Ruizhao Li
- Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou 510080, People's Republic of China.
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Sampogna RV, Al-Awqati Q. Taking a bite: endocytosis in the maintenance of the slit diaphragm. J Clin Invest 2012. [PMID: 23187132 DOI: 10.1172/jci65785] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In the kidney, the slit diaphragm joins adjacent podocytes, forming an epithelial barrier that filters plasma into the urinary space, yet retains blood cells and proteins within the circulation. In this issue of the JCI, Soda et al. have identified clathrin-mediated endocytosis as a central mechanism by which the function and structural integrity of the slit diaphragm are maintained.
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Affiliation(s)
- Rosemary V Sampogna
- Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
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Li M, Armelloni S, Edefonti A, Messa P, Rastaldi MP. Fifteen years of research on nephrin: what we still need to know. Nephrol Dial Transplant 2012; 28:767-70. [PMID: 23139403 DOI: 10.1093/ndt/gfs522] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- Min Li
- Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milano, Italy
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Kajiho Y, Harita Y, Kurihara H, Horita S, Matsunaga A, Tsurumi H, Kanda S, Sugawara N, Miura K, Sekine T, Hattori S, Hattori M, Igarashi T. SIRPα interacts with nephrin at the podocyte slit diaphragm. FEBS J 2012; 279:3010-21. [PMID: 22747997 DOI: 10.1111/j.1742-4658.2012.08682.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The slit diaphragm (SD) is an intercellular junction between renal glomerular epithelial cells (podocytes) that is essential for permselectivity in glomerular ultrafiltration. The SD components, nephrin and Neph1, assemble a signaling complex in a tyrosine phosphorylation dependent manner, and regulate the unique actin cytoskeleton of podocytes. Mutations in the NPHS1 gene that encodes nephrin cause congenital nephrotic syndrome (CNS), which is characterized by the loss of the SD and massive proteinuria. Recently, we have identified the expression of the transmembrane glycoprotein signal regulatory protein α (SIRPα) at the SD. In the present study, we analyzed the expression of SIRPα in developing kidneys, in kidneys from CNS patients and in proteinuric rat models. The possibility that SIRPα interacts with known SD proteins was also investigated. SIRPα was concentrated at the SD junction during the maturation of intercellular junctions. In the glomeruli of CNS patients carrying mutations in NPHS1, where SD formation is disrupted, the expression of SIRPα as well as Neph1 and nephrin was significantly decreased, indicating that SIRPα is closely associated with the nephrin complex. Indeed, SIRPα formed hetero-oligomers with nephrin in cultured cells and in glomeruli. Furthermore, the cytoplasmic domain of SIRPα was highly phosphorylated in normal glomeruli, and its phosphorylation was dramatically decreased upon podocyte injury in vivo. Thus, SIRPα interacts with nephrin at the SD, and its phosphorylation is dynamically regulated in proteinuric states. Our data provide new molecular insights into the phosphorylation events triggered by podocyte injury.
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Affiliation(s)
- Yuko Kajiho
- Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Japan
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