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1
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Cong F, Bao H, Wang X, Tang Y, Bao Y, Poulton JS, Liu X, Wong ACN, Ji X, Deng WM. Translocation of gut bacteria promotes tumor-associated mortality by inducing immune-activated renal damage. EMBO J 2025:10.1038/s44318-025-00458-5. [PMID: 40404992 DOI: 10.1038/s44318-025-00458-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 04/08/2025] [Accepted: 04/14/2025] [Indexed: 05/24/2025] Open
Abstract
Paraneoplastic syndrome represents severe and complex systemic clinical symptoms manifesting in multiple organs of cancer patients, but its cause and cellular underpinnings remain little explored. In this study, establishing a Drosophila model of paraneoplastic syndrome triggered by tumor transplantation, we found that the innate immune response, initiated by translocated commensal bacteria from a compromised intestine, significantly contributes to reduced lifespan in tumor-bearing hosts. Our data identify the renal system as a central hub of this paraneoplastic syndrome model, wherein the pericardial nephrocytes undergo severe damage due to an elevated immune response triggered by gut dysbiosis and bacterial translocation. This innate immune response-induced nephrocyte damage is a major contributor to reduced longevity in tumor-bearing hosts, as blocking the NF-kB/Imd pathway in nephrocytes or removing gut bacteria via germ-free derivation or antibiotic treatment ameliorates nephrocyte deterioration and extends the lifespan of tumor-bearing flies. Consistently, treatment with a detoxifying drug also extended the lifespan of the tumor hosts. Our findings highlight a critical role of the gut-kidney axis in the paraneoplastic complications observed in cancer-bearing flies, suggesting potential therapeutic targets for mitigating similar complications in cancer patients.
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Affiliation(s)
- Fei Cong
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA
| | - Hongcun Bao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA
| | - Xianfeng Wang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA
| | - Yang Tang
- Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Yuwei Bao
- Department of Mathematics, Tulane University School of Science & Engineering, New Orleans, LA, USA
| | - John S Poulton
- UNC Kidney Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiaowen Liu
- Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Adam Chun-Nin Wong
- Entomology and Nematology Department, University of Florida, Gainesville, FL, USA
- Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Xiang Ji
- Department of Mathematics, Tulane University School of Science & Engineering, New Orleans, LA, USA
| | - Wu-Min Deng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA.
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2
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Xiong Y, Li W, Jin S, Wan S, Wu S. Inflammation in glomerular diseases. Front Immunol 2025; 16:1526285. [PMID: 40103820 PMCID: PMC11913671 DOI: 10.3389/fimmu.2025.1526285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/12/2025] [Indexed: 03/20/2025] Open
Abstract
The structural and functional integrity of glomerular cells is critical for maintaining normal kidney function. Glomerular diseases, which involve chronic histological damage to the kidney, are related to injury to glomerular cells such as endothelial cells, mesangial cells (MCs), and podocytes. When faced with pathogenic conditions, these cells release pro-inflammatory cytokines such as chemokines, inflammatory factors, and adhesion factors. These substances interact with glomerular cells through specific inflammatory pathways, resulting in damage to the structure and function of the glomeruli, ultimately causing glomerular disease. Although the role of inflammation in chronic kidney diseases is well known, the specific molecular pathways that result in glomerular diseases remain largely unclear. For a long time, it has been believed that only immune cells can secrete inflammatory factors. Therefore, targeted therapies against immune cells were considered the first choice for treating inflammation in glomerular disease. However, emerging research indicates that non-immune cells such as glomerular endothelial cells, MCs, and podocytes can also play a role in renal inflammation by releasing inflammatory factors. Similarly, targeted therapies against glomerular cells should be considered. This review aims to uncover glomerular diseases related to inflammation and pathways in glomerular inflammation, and for the first time summarized that non-immune cells in the glomerulus can participate in glomerular inflammatory damage by secreting inflammatory factors, providing valuable references for future strategies to prevent and treat glomerular diseases. More importantly, we emphasized targeted glomerular cell therapy, which may be a key direction for the future treatment of glomerular diseases.
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Affiliation(s)
- Yongqing Xiong
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Wei Li
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Songzhi Jin
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Shujing Wan
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Suzhen Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
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3
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Roye Y, Miller C, Kalejaiye TD, Musah S. A human stem cell-derived model reveals pathologic extracellular matrix remodeling in diabetic podocyte injury. Matrix Biol Plus 2024; 24:100164. [PMID: 39582511 PMCID: PMC11585791 DOI: 10.1016/j.mbplus.2024.100164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/16/2024] [Accepted: 10/27/2024] [Indexed: 11/26/2024] Open
Abstract
Diabetic nephropathy results from chronic (or uncontrolled) hyperglycemia and is the leading cause of kidney failure. The kidney's glomerular podocytes are highly susceptible to diabetic injury and subsequent non-reversible degeneration. We generated a human induced pluripotent stem (iPS) cell-derived model of diabetic podocytopathy to investigate disease pathogenesis and progression. The model recapitulated hallmarks of podocytopathy that precede proteinuria including retraction of foot processes and podocytopenia (detachment from the extracellular matrix (ECM)). Moreover, hyperglycemia-induced injury to podocytes exacerbated remodeling of the ECM. Specifically, mature podocytes aberrantly increased expression and excessively deposited collagen (IV)α1α1α2 that is normally abundant in the embryonic glomerulus. This collagen (IV) imbalance coincided with dysregulation of lineage-specific proteins, structural abnormalities of the ECM, and podocytopenia - a mechanism not shared with endothelium and is distinct from drug-induced injury. Intriguingly, repopulation of hyperglycemia-injured podocytes on decellularized ECM scaffolds isolated from healthy podocytes attenuated the loss of synaptopodin (a mechanosensitive protein associated with podocyte health). These results demonstrate that human iPS cell-derived podocytes can facilitate in vitro studies to uncover the mechanisms of chronic hyperglycemia and ECM remodeling and guide disease target identification.
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Affiliation(s)
- Yasmin Roye
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA
| | - Carmen Miller
- Department of Biology, Trinity College of Arts and Sciences, Duke University, Durham NC, USA
| | - Titilola D. Kalejaiye
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA
| | - Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA
- Department of Medicine, Division of Nephrology, Duke University School of Medicine, Durham, NC, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC, USA
- Affiliate Faculty of the Developmental and Stem Cell Biology Program, Duke University School of Medicine, Durham, NC, USA
- MEDx Investigator, Duke University, Durham, NC, USA
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4
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Williamson CR, Jones N. Reduced Nephrin Tyrosine Phosphorylation Enhances Insulin Secretion and Increases Glucose Tolerance With Age. Endocrinology 2024; 165:bqae078. [PMID: 38954536 PMCID: PMC11247170 DOI: 10.1210/endocr/bqae078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/31/2024] [Accepted: 06/27/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. METHODS To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. RESULTS Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. CONCLUSION Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function.
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Affiliation(s)
- Casey R Williamson
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Nina Jones
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
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5
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Cara-Fuentes G, Andres-Hernando A, Bauer C, Banks M, Garcia GE, Cicerchi C, Kuwabara M, Shimada M, Johnson RJ, Lanaspa MA. Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood. iScience 2022; 25:104694. [PMID: 35847557 PMCID: PMC9284382 DOI: 10.1016/j.isci.2022.104694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 05/23/2022] [Accepted: 06/24/2022] [Indexed: 01/21/2023] Open
Abstract
Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.
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Affiliation(s)
| | - Ana Andres-Hernando
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA
| | - Colin Bauer
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Mindy Banks
- Rocky Mountain Pediatric Kidney Center, Denver, CO, USA
| | - Gabriela E. Garcia
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Christina Cicerchi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Masanari Kuwabara
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Michiko Shimada
- Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Miguel A. Lanaspa
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA,Corresponding author
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6
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Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf) 2022; 235:e13850. [PMID: 35716094 DOI: 10.1111/apha.13850] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/23/2022] [Accepted: 06/13/2022] [Indexed: 01/19/2023]
Abstract
Selective glomerular filtration relies on the membrane separating the glomerular arterioles from the Bowman space. As a major component of the glomerular filtration barrier, podocytes form foot processes by the actin cytoskeleton, which dynamically adjusts in response to environmental changes to maintain filtration barrier integrity. The slit diaphragms bridge the filtration slits between neighboring foot processes and act as signaling hubs interacting with the actin cytoskeleton. Focal adhesions relay signals to regulate actin dynamics while allowing podocyte adherence to the basement membrane. Mutations in actin regulatory and signaling proteins may disrupt the actin cytoskeleton, resulting in foot process retraction, effacement, and proteinuria. Large-scale gene expression profiling platforms, transgenic animal models, and other in vivo gene delivery methods now enhance our understanding of the interactions among podocyte focal adhesions, slit diaphragms, and actin dynamics. In addition, our team found that at least 66% of idiopathic nephrotic syndrome (INS) children have podocyte autoantibodies, which was defined as a new disease subgroup-, autoimmune podocytopathies. This review outlines the pathophysiological mechanisms of podocyte cytoskeleton protein interactions in proteinuria and glomerular podocytopathy.
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Affiliation(s)
- Qing Ye
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Bing Lan
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Huihui Liu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Pontus B Persson
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Translational Physiology, Berlin, Germany
| | - En Yin Lai
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Translational Physiology, Berlin, Germany.,Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
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7
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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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Jiang B, Zhang Y, Wang Y, Li Z, Chen Q, Tang J, Zhu G. Glibenclamide Attenuates Neuroinflammation and Promotes Neurological Recovery After Intracerebral Hemorrhage in Aged Rats. Front Aging Neurosci 2021; 13:729652. [PMID: 34512312 PMCID: PMC8427510 DOI: 10.3389/fnagi.2021.729652] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/21/2021] [Indexed: 11/13/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a common disease in the elderly population. Inflammation following ICH plays a detrimental role in secondary brain injury, which is associated with a poor prognosis of patients with ICH, and no efficient pharmacological preventions are available. Here, we investigated the effects of glibenclamide (GLC) on neuroinflammation in an autoblood-induced aged rat (18 months old) model of ICH. Rats were randomized into the sham, vehicle, and GLC groups. First, we investigated the expression level of sulfonylurea receptor 1 (Sur1) surrounding the hematoma after ICH. Then, neurological scores were calculated, and water maze tests, brain water content analysis, western blotting, and immunofluorescence assays were implemented to detect the neuroprotective effect of GLC. The expression of the Sur1-Trpm4 channel was significantly increased in the perihematomal tissue following ICH in aged rats. The GLC administration effectively reduced brain edema and improved neurofunction deficits following ICH. In addition, GLC increased the expression of brain-derived neurotrophic factors and decreased the expression of proinflammatory factors [tumor necrosis factor (TNF)-α,interleukin (IL)-1, and IL-6]. Moreover, GLC markedly reduced Ikappa-B (IκB) kinase (IKK) expression in microglia and nuclear factor (NF)-κB-P65 levels in perihematomal tissue. GLC ameliorated ICH-induced neuroinflammation and improved neurological outcomes in aged rats. In part, GLC may exert these effects by regulating the NF-κB signaling pathway through the Sur1-Trpm4 channel.
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Affiliation(s)
- Bing Jiang
- Department of Neurology, Chengdu Fifth People's Hospital, Chengdu, China
| | - Ying Zhang
- Department of Neurology, Chengdu Fifth People's Hospital, Chengdu, China
| | - Yan Wang
- Department of Neurology, Chengdu Fifth People's Hospital, Chengdu, China
| | - Zheng Li
- Department of Neurology, Chengdu Fifth People's Hospital, Chengdu, China
| | - Qianwei Chen
- Department of Neurosurgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jun Tang
- Department of Neurosurgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Gang Zhu
- Department of Neurosurgery, Southwest Hospital, Army Medical University, Chongqing, China
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9
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Xiong Y, Zhu W, Xu Q, Ruze R, Yan Z, Li J, Hu S, Zhong M, Cheng Y, Zhang G. Sleeve Gastrectomy Attenuates Diabetic Nephropathy by Upregulating Nephrin Expressions in Diabetic Obese Rats. Obes Surg 2021; 30:2893-2904. [PMID: 32399849 DOI: 10.1007/s11695-020-04611-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and sleeve gastrectomy (SG) is considered to be an effective strategy to improve pre-existing DN. However, the mechanism remains unknown. MATERIALS AND METHODS Animal model of DN was induced by high-fat diet (HFD) and streptozotocin (STZ). SG or sham surgery was performed and rats were sacrificed at 4, 8, and 12 weeks after surgery. The basic parameters (blood glucose, body weight, kidney weight), indicators of renal function including serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin, urine creatinine (Ucr), microalbumin creatinine ratio (UACR), ultrastructural changes of glomerulus, and the expression of nephrin gene and protein in glomerular podocytes were compared among groups. RESULTS Blood glucose and body weight of SG rats were significantly lower than those of the sham-operated rats, and renal function of SG groups were also significantly improved within the postoperative period of 12 weeks. The results of periodic acid-Schiff staining (PAS) and transmission electron microscopy (TEM) showed that glomerular hypertrophy and accumulation of extracellular matrix proteins were significantly alleviated after SG, and the thickness of basement membrane and the fusion or effacement of foot processes were also significantly improved. The mRNA and protein expression of nephrin in SG groups was significantly higher than that in the sham group. CONCLUSION These results suggest that SG attenuates DN by upregulating the expression of nephrin and improving the ultrastructure of glomerular filtration membrane. This study indicates that SG can be used as an available therapeutic intervention for DN.
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Affiliation(s)
- Yacheng Xiong
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong Province, People's Republic of China
| | - Wei Zhu
- Shandong Medical College, Jucai 6# Road, Linyi, 276000, Shandong Province, People's Republic of China
| | - Qian Xu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong Province, People's Republic of China
| | - Rexiati Ruze
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong Province, People's Republic of China
| | - Zhibo Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Jianwen Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, 16766#, Jingshi Road, Jinan, 250014, Shandong Province, China
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, 16766#, Jingshi Road, Jinan, 250014, Shandong Province, China
| | - Yugang Cheng
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, 16766#, Jingshi Road, Jinan, 250014, Shandong Province, China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, 16766#, Jingshi Road, Jinan, 250014, Shandong Province, China.
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10
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Lehtonen S. Metformin Protects against Podocyte Injury in Diabetic Kidney Disease. Pharmaceuticals (Basel) 2020; 13:ph13120452. [PMID: 33321755 PMCID: PMC7764076 DOI: 10.3390/ph13120452] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/06/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of metformin on podocytes, the glomerular epithelial cells that are central in maintaining the glomerular ultrafiltration function.
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Affiliation(s)
- Sanna Lehtonen
- Research Program for Clinical and Molecular Metabolism and Department of Pathology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
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11
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Tian X, Inoue K, Zhang Y, Wang Y, Sperati CJ, Pedigo CE, Zhao T, Yan M, Groener M, Moledina DG, Ebenezer K, Li W, Zhang Z, Liebermann DA, Greene L, Greer P, Parikh CR, Ishibe S. Inhibiting calpain 1 and 2 in cyclin G associated kinase-knockout mice mitigates podocyte injury. JCI Insight 2020; 5:142740. [PMID: 33208557 PMCID: PMC7710277 DOI: 10.1172/jci.insight.142740] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/08/2020] [Indexed: 12/27/2022] Open
Abstract
Evidence for reduced expression of cyclin G associated kinase (GAK) in glomeruli of patients with chronic kidney disease was observed in the Nephroseq human database, and GAK was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak-knockout mice (Gak-KO), which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mice carrying the mutation to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to progressive podocyte damage. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak-KO mice. Podocyte-specific deletion of Capns1, essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak-KO mice. Increased podocyte calpain activity-mediated proteolysis of IκBα resulted in increased NF-κB p65-induced expression of growth arrest and DNA-damage-inducible 45 beta in the Gak-KO mice. Our results suggest that loss of podocyte-associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.
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MESH Headings
- Animals
- Calpain/antagonists & inhibitors
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/pathology
- Diabetic Nephropathies/therapy
- Female
- Glomerulosclerosis, Focal Segmental/etiology
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/therapy
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Podocytes/metabolism
- Podocytes/pathology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Protein Serine-Threonine Kinases/physiology
- Renal Insufficiency, Chronic/etiology
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Renal Insufficiency, Chronic/therapy
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Affiliation(s)
- Xuefei Tian
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kazunori Inoue
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yan Zhang
- State Key Laboratory of Organ Failure Research, Southern Medical University, Nanfang Hospital, Guangzhou, China
- Center for Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ying Wang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - C. John Sperati
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher E. Pedigo
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Tingting Zhao
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Meihua Yan
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Marwin Groener
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Dennis G. Moledina
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Karen Ebenezer
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Wei Li
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Zhenhai Zhang
- State Key Laboratory of Organ Failure Research, Southern Medical University, Nanfang Hospital, Guangzhou, China
- Center for Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Dan A. Liebermann
- Fels Institute of Cancer Research and Molecular Biology and Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania USA
| | - Lois Greene
- Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Peter Greer
- Queen’s Cancer Research Institute, Kingston, Ontario, Canada
| | - Chirag R. Parikh
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shuta Ishibe
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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Wang Y, Chen L, Wang K, Da Y, Zhou M, Yan H, Zheng D, Zhong S, Cai S, Zhu H, Li Y. Suppression of TRPM2 reduces renal fibrosis and inflammation through blocking TGF-β1-regulated JNK activation. Biomed Pharmacother 2019; 120:109556. [PMID: 31655312 DOI: 10.1016/j.biopha.2019.109556] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Chronic kidney disease (CKD) is a major cause of death. Renal fibrosis and inflammation are common pathways contributing to the development of this disease. However, the molecular mechanisms underlying CKD are not fully understood. TRPM2 (Transient receptor potential melastatin-2) was previously identified as a potential target in various diseases due to its multiple functions. In the study, mice with unilateral urethral obstruction (UUO) were used to explore the effects of TRPM2 on renal injury. First, TRPM2 expression was up-regulated in kidney of mice after UUO. Renal histological analysis using H&E and PAS staining showed that histological changes induced by UUO were markedly alleviated in TRPM2-deficient mice. In addition, TRPM2 knockout markedly improved renal dysfunction, as evidenced by the reduced serum creatine, blood urea nitrogen (BUN), kidney injury molecule 1 (KIM-1) expression and enhanced Nephrin levels. TRPM2 ablation significantly attenuated renal interstitial fibrosis in mice with UUO via decreasing transforming growth factor (TGF)-β1 expression, accompanied with the reduction of fibrotic genes, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin (FN) and Collagen 1 alpha 1 (Col1α1). Suppressing TRPM2 expression also suppressed inflammatory cell infiltration and release of pro-inflammatory factors in UUO-triggered renal fibrosis. Further, TRPM2 deficiency inhibited IκBα/nuclear factor (NF)-κB signaling in UUO-treated mice. Moreover, c-Jun N-terminal kinase (JNK) signaling was blocked by TRPM2 knockout in UUO mice. Surprisingly, the in vitro results indicated that blocking JNK activation resulted in the suppression of TGF-β1-induced fibrosis and inflammation. Together, these findings demonstrate that the inhibition of TRPM2 might protect against renal fibrosis and inflammation through impeding JNK activation regulated by TGF-β1.
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Affiliation(s)
- Ying Wang
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Lingwei Chen
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Kangyao Wang
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China.
| | - Yuanting Da
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Min Zhou
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Haihong Yan
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Dan Zheng
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Sen Zhong
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Shasha Cai
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Huiping Zhu
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
| | - Yunsheng Li
- Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China
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Arfian N, Setyaningsih WAW, Anggorowati N, Romi MM, Sari DCR. Ethanol Extract of Centella asiatica (Gotu Kola) Attenuates Tubular Injury Through Inhibition of Inflammatory Cytokines and Enhancement of Anti-Fibrotic Factor in Mice with 5/6 Subtotal Nephrectomy. Malays J Med Sci 2019; 26:53-63. [PMID: 31728118 PMCID: PMC6839655 DOI: 10.21315/mjms2019.26.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/15/2019] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) leads to inflammation, fibrosis and destruction of the renal architecture. Centella asiatica (CeA) is an herbaceous plant with anti-inflammatory effects. We aimed to elucidate the effect of CeA on inflammation, fibrosis, vascular remodelling and antifibrotic substances in a 5/6 subtotal nephrectomy (SN) model in mice. METHODS Mice were divided into three groups: sham operation (SO, n = 6), 5/6 SN for seven days (SN7, n = 7) and SN7 with oral CeA treatment (SN7-CeA, n = 7). At day 7, mice were euthanised, kidneys were harvested and stained with periodic-acid Schiff (for tubular injury and glomerulosclerosis) and sirius red (for fibrosis and vascular remodeling) staining. mRNA expression of prepro-endothelin-1, nephrin, E-cadherin, bone morphogenic protein-7 (BMP-7), toll-like receptor 4 (TLR4), tumour necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) were quantified using reverse transcriptase-PCR. RESULTS SN group demonstrated significant higher interstitial fibrosis, vascular remodeling, tubular injury and glomerulosclerosis (P < 0.01) compared to SO group. Meanwhile, in SN7-CeA demonstrated attenuation of vascular remodeling as shown by significant higher lumen area with lower Wall/Lumen area ratio compared to SN7. RT-PCR analysis showed up-regulation of nephrin, BMP-7 and E-cadherin mRNA expression (P < 0.05) and down-regulation of ppET-1 in SN7-CeA group compared to SN7 group (P < 0.05). CONCLUSION CeA may ameliorate renal injury in the SN model in mice.
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Affiliation(s)
- Nur Arfian
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | | | - Nungki Anggorowati
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Muhammad Mansyur Romi
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dwi Cahyani Ratna Sari
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
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Samsu N, Soeharto S, Rifai M, Rudijanto A. Rosmarinic acid monotherapy is better than the combination of rosmarinic acid and telmisartan in preventing podocyte detachment and inhibiting the progression of diabetic nephropathy in rats. Biologics 2019; 13:179-190. [PMID: 31564826 PMCID: PMC6722456 DOI: 10.2147/btt.s214820] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/19/2019] [Indexed: 02/02/2023]
Abstract
BACKGROUND Podocyte injury and its subsequent detachment play a critical role in the development and progression of diabetic nephropathy (DN). The objective of this study was to investigate the effect of rosmarinic acid (RA) in preventing podocyte detachment and inhibiting the progression of DN in streptozotocin (STZ)-induced diabetic in rats. METHODS We used 20 adult male Wistar rats as experimental animals, which were randomly divided into 5 groups (n=4 per group): nondiabetic rat group (negative control) and 4 groups of STZ-induced diabetic rats, namely, 1 group untreated diabetic rats (positive control) and 3 groups treated diabetic rats with RA 75 mg/kg, telmisartan (TMS) 1 mg/kg and combination of RA 75 mg/kg with TMS 1 mg/kg), respectively. After 8 weeks of therapy, urinary levels of podocin, nephrin and albumin and also serum cystatin C levels were examined by ELISA. The expression of p65 nuclear factor-kB by immunohistochemistry whereas expression of podocin and nephrin glomerulus were examined by immunofluorescence. RESULTS In the treated diabetic groups, we found that urinary level of podocin and nephrin, albumin urine excretion and serum cystatin C levels were significantly lower than the positive control group. Compared to negative controls, the group of treated diabetic rats did not differ significantly in preventing increased excretion of urinary nephrin and podocin. Meanwhile, treatment with RA monotherapy was significantly better than TMS or a combination of RA with TMS in reducing albumin excretion and preventing decreased kidney function. CONCLUSION In STZ-induced diabetic rats, RA can prevent podocyte detachment. Treatment with RA and TMS either monotherapy or in combination can inhibit the development and progression of DN. However, the combination of both did not show a synergistic effect, even have higher urinary albumin excretion and worse kidney function compared to the RA monotherapy.
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Affiliation(s)
- Nur Samsu
- Department of Internal Medicine, Division of Nephrology and Hypertension, Faculty of Medicine
| | | | - Muhaimin Rifai
- Department of Biology, Faculty of Mathematics and Sciences
| | - Achmad Rudijanto
- Department of Internal Medicine, Division of Endocrinology and Metabolic, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
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15
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Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis. PLoS One 2019; 14:e0216426. [PMID: 31095586 PMCID: PMC6522053 DOI: 10.1371/journal.pone.0216426] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/20/2019] [Indexed: 01/09/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is frequently found in biopsies of patients with steroid resistant nephrotic syndrome (SRNS). The pathogenesis of SRNS/FSGS is often unknown and the disease will recur in up to 50% of patients post-transplant, indicating the presence of circulating podocyte-toxic factor(s). Several studies have reported clinical improvement after anti-TNFα therapy. However, prediction of the clinical outcome in SRNS/FSGS is difficult, and novel predictive biomarkers are needed. An image-based assay, which measures disassembly of focal adhesion complexes in cultured podocytes, was used to ascertain the presence of podocyte toxic activity in SRNS/FSGS sera. Expression of TNFα pathway genes was analysed in the Nephroseq FSGS cohort and in cultured podocytes treated with SRNS/FSGS sera. Podocyte toxic activity was detected in 48/96 SRNS/FSGS patients. It did not correlate with serum TNFα levels, age, sex, ethnicity or glomerular filtration rate. In ~25% of the toxic samples, the toxicity was strongly inhibited by blockade of TNFα signaling. Transcriptional profiling of human FSGS biopsies and podocytes treated with FSGS sera revealed significant increases in expression of TNFα pathway genes. We identified patients with serum podocyte toxic activity who may be at risk for FSGS recurrence, and those patients in whom serum podocyte toxicity may be reversed by TNFα blockade. Activation of TNFα pathway genes occurs in podocytes of FSGS patients suggesting a causative effect of this pathway in response to circulating factor(s). In vitro analyses of patient sera may stratify patients according to prognostic outcomes and potential responses to specific clinical interventions.
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Li L, Liu Y, Li S, Yang R, Zeng C, Rong W, Liang H, Zhang M, Zhu X, Kidder K, Liu Y, Liu Z, Zen K. Signal regulatory protein α protects podocytes through promoting autophagic activity. JCI Insight 2019; 5:124747. [PMID: 30888336 DOI: 10.1172/jci.insight.124747] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
High autophagic activity in podocytes, terminally differentiated cells which serve as main components of the kidney filtration barrier, is essential for podocyte survival under various challenges. How podocytes maintain such a high level of autophagy, however, remains unclear. Here we report that signal regulatory protein α (SIRPα) plays a key role in promoting podocyte autophagy. Unlike other glomerular cells, podocytes strongly express SIRPα, which is, however, downregulated in patients with focal segmental glomerulosclerosis and mice with experimental nephropathy. Podocyte SIRPα levels are inversely correlated with the severity of podocyte injury and proteinuria but positively with autophagy. Compared to wild-type littermates, Sirpa-deficient mice display greater age-related podocyte injury and proteinuria and develop more rapid and severe renal injury in various models of experimental nephropathy. Mechanistically, podocyte SIRPα strongly reduces Akt/GSK-3β/β-catenin signaling, leading to an increase in autophagic activity. Our findings thus demonstrate a critical protective role of SIRPα in podocyte survival via maintaining autophagic activity.
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Affiliation(s)
- Limin Li
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
| | - Ying Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
| | - Shan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
| | - Rong Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Weiwei Rong
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
| | - Hongwei Liang
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China.,Center for Inflammation, Immunity and Infection, Program of Cell and Molecular Immunology, Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Mingchao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Koby Kidder
- Center for Inflammation, Immunity and Infection, Program of Cell and Molecular Immunology, Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Yuan Liu
- Center for Inflammation, Immunity and Infection, Program of Cell and Molecular Immunology, Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, China
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17
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APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress. Biosci Rep 2018; 38:BSR20171713. [PMID: 29967295 PMCID: PMC6131197 DOI: 10.1042/bsr20171713] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 06/12/2018] [Accepted: 07/02/2018] [Indexed: 12/31/2022] Open
Abstract
Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.
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18
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Abstract
Ultimately, the common final pathway of any glomerular disease is podocyte effacement, podocyte loss, and, eventually, glomerular scarring. There has been a long-standing debate on the underlying mechanisms for podocyte depletion, ranging from necrosis and apoptosis to detachment of viable cells from the glomerular basement membrane. However, this debate still continues because additional pathways of programmed cell death have been reported in recent years. Interestingly, viable podocytes can be isolated out of the urine of proteinuric patients easily, emphasizing the importance of podocyte detachment in glomerular diseases. In contrast, detection of apoptosis and other pathways of programmed cell death in podocytes is technically challenging. In fact, we still are lacking direct evidence showing, for example, the presence of apoptotic bodies in podocytes, leaving the question unanswered as to whether podocytes undergo mechanisms of programmed cell death. However, understanding the mechanisms leading to podocyte depletion is of particular interest because future therapeutic strategies might interfere with these to prevent glomerular scarring. In this review, we summarize our current knowledge on podocyte cell death, the different molecular pathways and experimental approaches to study these, and, finally, focus on the mechanisms that prevent the onset of programmed cell death.
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Affiliation(s)
- Fabian Braun
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany
| | - Jan U Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Paul T Brinkkoetter
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany.
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19
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Martin CE, Jones N. Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond. Front Endocrinol (Lausanne) 2018; 9:302. [PMID: 29922234 PMCID: PMC5996060 DOI: 10.3389/fendo.2018.00302] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/22/2018] [Indexed: 12/11/2022] Open
Abstract
Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.
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20
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Wu J, He Y, Luo Y, Zhang L, Lin H, Liu X, Liu B, Liang C, Zhou Y, Zhou J. MiR-145-5p inhibits proliferation and inflammatory responses of RMC through regulating AKT/GSK pathway by targeting CXCL16. J Cell Physiol 2017; 233:3648-3659. [PMID: 29030988 DOI: 10.1002/jcp.26228] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 10/09/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Junbiao Wu
- Department of Clinical Pharmacy; The Second Affiliated Hospital; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
- Postdoctoral Scientific Research of Guangzhou University of Chinese Medicine; Guangzhou; Guangdong P.R. China
| | - Yu He
- School of Pharmaceutical Sciences; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Yining Luo
- Department of Clinical Pharmacy; The Second Affiliated Hospital; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Lei Zhang
- Department of Nephrology; The Second Affiliated Hospital; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Hua Lin
- Department of Clinical Pharmacy; The Second Affiliated Hospital; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Xusheng Liu
- Department of Nephrology; The Second Affiliated Hospital; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Bihao Liu
- School of Pharmaceutical Sciences; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Chunling Liang
- Section of Immunology & Chinese Medicine; The Second Affiliated Hospital of Guangzhou University of Chinese; Guangzhou Guangdong P.R. China
| | - Yuan Zhou
- School of Pharmaceutical Sciences; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
| | - Jiuyao Zhou
- School of Pharmaceutical Sciences; Guangzhou University of Chinese Medicine; Guangzhou Guangdong P.R. China
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21
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Li X, Gao Z, Gao H, Li B, Peng T, Jiang B, Yang X, Hu Z. Nephrin loss is reduced by grape seed proanthocyanidins in the experimental diabetic nephropathy rat model. Mol Med Rep 2017; 16:9393-9400. [PMID: 29152654 PMCID: PMC5779996 DOI: 10.3892/mmr.2017.7837] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 08/31/2017] [Indexed: 01/10/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the major causes of end-stage renal failure. Grape seed proanthocyanidin extracts (GSPE) are known to act as antioxidants. The current study aimed to determine the effects of GSPE on the streptozotocin (STZ)-induced diabetic rat model and to explore the underlying mechanism of its action. Wistar rats were induced into a diabetic state by injection of STZ and were treated with 250 mg·kg−1·day−1 GSPE for 24 weeks. Kidney samples were collected for observation of renal pathological changes by light microscope (periodic acid-Schiff staining) and electron microscopy. Reverse transcription-polymerase chain reaction, western blotting, and immunohistochemical staining were used to detect the mRNA and protein expression of the receptor for advanced glycation end-products (RAGE), nephrin and podocin. The results indicated that diabetic rats treated with GSPE had markedly reduced Ccr, urinary albumin excretion, ratio of kidney weight to body weight, AGEs and ECM accumulation (P<0.01) compared with that in the diabetic rats. GSPE treatment can also reverse the renal pathological damage in diabetic rats. Further results indicated that GSPE treatment significantly decreased the RAGE expression level (P<0.01), and significantly increased the expression level of nephrin in the kidney and glomeruli of diabetic rats (P<0.01). However, no significant differences were identified in the expression of podocin following GSPE treatment (P>0.05). In conclusion, the results demonstrated that GSPE exerts a reno-protective effect by decreasing urinary albumin excretion and reversing renal pathological damage in diabetic rats. The underlying mechanism of GSPE activity is associated with the decreased expression of the AGEs/RAGE axis and the increased expression of nephrin in diabetic rats.
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Affiliation(s)
- Xianhua Li
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhaoli Gao
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Haiqing Gao
- Department of Geriatrics, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Baoying Li
- Department of Geriatrics, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Tao Peng
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Bei Jiang
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiangdong Yang
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhao Hu
- Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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22
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Available and incoming therapies for idiopathic focal and segmental glomerulosclerosis in adults. J Nephrol 2017; 31:37-45. [DOI: 10.1007/s40620-017-0402-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 04/10/2017] [Indexed: 01/30/2023]
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23
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Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017. [PMID: 28639250 DOI: 10.1007/5584_2017_62] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Diabetes is the leading cause of microalbuminuria and end-stage renal failure in industrial countries. Disruption of the filtration barrier, seen in almost all nephrotic diseases and diabetes, is the result of the loss or effacement of the podocyte foot process, notably damage of proteins within the slit diaphragm such as nephrin. For many years, nephrin has been viewed as a structural component of the slit diaphragm. It is now well recognized that nephrin contains several tyrosine residues in its cytoplasmic domain, which influences the development of glomerular injury. In this review, we propose an overview of nephrin signaling pathways in kidney injury.
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Podocyte-specific NF-κB inhibition ameliorates proteinuria in adriamycin-induced nephropathy in mice. Clin Exp Nephrol 2016; 21:16-26. [PMID: 27089875 DOI: 10.1007/s10157-016-1268-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 04/10/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in proteinuria. In the present study, we sought to determine the cell-autonomous role of NF-κB, a proinflammatory signaling, within podocytes in proteinuric kidney disease. METHODS Podocyte-specific IκBΔN transgenic (Pod-IκBΔN) mice, in which NF-κB was inhibited specifically in podocytes, were generated by the Cre-loxP technology, and their phenotype was compared with control mice in adriamycin-induced nephropathy. RESULTS Pod-IκBΔN mice were phenotypically normal and did not exhibit proteinuria at the physiological condition. By the intravenous administration of adriamycin, overt proteinuria appeared in Pod-IκBΔN mice, as well as in control mice. However, of interest, the amount of proteinuria was significantly lower in adriamycin-injected Pod-IκBΔN mice (373 ± 122 mg albumin/g creatinine), compared with adriamycin-injected control mice (992 ± 395 mg albumin/g creatinine). Expression of podocyte-selective slit diaphragm-associated proteins, such as nephrin and synaptopodin, was markedly decreased by adriamycin injection in control mice, whereas the reduction was attenuated in Pod-IκBΔN mice. Adriamycin-induced reduction in synaptopodin expression was also seen in cultured podocytes derived from control mice, but not in those from Pod-IκBΔN mice. CONCLUSIONS Because nephrin and synaptopodin are essential for the maintenance of the slit diaphragm in podocytes, these results suggest that proteinuria in adriamycin-induced nephropathy is caused by the reduction in expression of these proteins. The results also suggest that the NF-κB signalling in podocytes cell-autonomously contributes to proteinuria through the regulation of these proteins.
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Huang F, Wang Q, Ma X, Wu L, Guo F, Qin G. Valsartan inhibits amylin-induced podocyte damage. Microvasc Res 2016; 106:101-9. [PMID: 27102209 DOI: 10.1016/j.mvr.2016.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 03/19/2016] [Accepted: 04/16/2016] [Indexed: 01/01/2023]
Abstract
Previous studies have described the deposition of amylin in the kidney of patients with type 2 diabetes mellitus (T2DM). These deposits play a critical role in the pathogenesis of diabetic nephropathy (DN), although the mechanism underlying this effect is unknown. Thus, this study was undertaken to investigate whether amylin aggregation stimulates the local angiotensin II type 1 receptor (AT1R) in podocytes, and to examine its role in podocyte apoptosis. Amylin-induced apoptosis was investigated in vitro in differentiated, conditionally immortalized mouse podocytes and in vivo in KM mice. Expression of genes including nephrin, podocin, AT1R and desmin was measured through quantitative real time PCR, western blot and immunohistochemistry. Apoptosis was determined by flow cytometry, while the cellular distribution of podocin and nephrin was investigated by immunofluorescence. The ultra-structure of glomeruli was examined by transmission electron microscopy (TEM). Amylin enhanced apoptosis in a dose-dependent manner in vitro. The peptide also suppressed podocin and nephrin expression, but enhanced that of AT1R and desmin. Both effects were significantly blocked by valsartan, which inhibits angiotensin II type 1 receptor. These findings suggest that amylin activates a local intracellular RAS in podocytes and induces damage and apoptosis.
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Affiliation(s)
- Fengjuan Huang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Qingzhu Wang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xiaojun Ma
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Lina Wu
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Feng Guo
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Guijun Qin
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Lin X, You Y, Wang J, Qin Y, Huang P, Yang F. MicroRNA-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy. Inflammation 2015; 38:546-54. [PMID: 24969676 DOI: 10.1007/s10753-014-9961-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
MiR-155 has been reported to be involved in both innate and adaptive immune responses. But the role of miR-155 in hyperglycemia-induced nephropathy is still unknown. In our current study, 3-month-old male wild-type C57 mice and Mir-155(-/-) mice were used to establish hyperglycemia-induced nephropathy. In our hyperglycemia-induced nephropathy model, the expression of podocyte injury marker desmin was markedly increased in the diabetes group when compared with control. Diabetes also significantly decreased the levels of nephrin and acetylated nephrin, whereas the expression of miR-155 was markedly increased in diabetes group when compared with control. MiR-155(-/-) mice showed significantly increased expression of nephrin, acetylated nephrin, and Wilm's tumor-1 protein (WT-1) when compared with wild-type control. MiR-155 deficiency results in significantly decrease in IL-17A expression both in vivo and in vitro. And the increased expression of WT-1, nephrin, and ac-nephrin was reversed with additional treatment of rmIL-17. Furthermore, we found that the inhibited Th17 differentiation induced by miR-155 deficiency was dependent on increased expression of SOCS1. In conclusion, miR-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy. This was associated with inhibited IL-17 production through enhancement of SOCS1 expression.
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Affiliation(s)
- Xu Lin
- Department of Nephrology, the Affiliated Hospital of Youjiang Medical University for Nationalities, 18 Zhongshan Road, Baise, China
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Abstract
Nuclear factor κB (NF-κB) is a family of inducible transcription factors that plays a vital role in different aspects of immune responses. NF-κB is normally sequestered in the cytoplasm as inactive complexes via physical association with inhibitory proteins termed IκBs. In response to immune and stress stimuli, NF-κB members become activated via two major signaling pathways, the canonical and noncanonical pathways, and move to the nucleus to exert transcriptional functions. NF-κB is vital for normal immune responses against infections, but deregulated NF-κB activation is a major cause of inflammatory diseases. Accumulated studies suggest the involvement of NF-κB in the pathogenesis of renal inflammation caused by infection, injury, or autoimmune factors. In this review, we discuss the current understanding regarding the activation and function of NF-κB in different types of kidney diseases.
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Affiliation(s)
- Haisong Zhang
- />Department of Nephrology, Affiliated Hospital of Hebei University, No. 213 Yuhuadonglu, Baoding, 071000 China
| | - Shao-Cong Sun
- />Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030 USA
- />The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030 USA
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Huaiqihuang Granules () reduce proteinuria by enhancing nephrin expression and regulating necrosis factor κB signaling pathway in adriamycin-induced nephropathy. Chin J Integr Med 2015; 23:279-287. [PMID: 26453563 DOI: 10.1007/s11655-015-2293-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms. METHODS Rats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers. RESULTS HQH ameliorated the rat's general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis. CONCLUSION HQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.
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Kaneko K, Tsuji S, Kimata T, Kitao T, Yamanouchi S, Kato S. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes. World J Pediatr 2015; 11:21-8. [PMID: 25822700 DOI: 10.1007/s12519-015-0003-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 07/11/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome. DATA SOURCES This article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words "pathogenesis", "minimal change nephrotic syndrome" or "idiopathic nephrotic syndrome". RESULTS Unknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4. CONCLUSIONS Recent evidence suggests that minimal-change disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease.
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Affiliation(s)
- Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan,
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Zhao X, Hsu KS, Lim JH, Bruggeman LA, Kao HY. α-Actinin 4 potentiates nuclear factor κ-light-chain-enhancer of activated B-cell (NF-κB) activity in podocytes independent of its cytoplasmic actin binding function. J Biol Chem 2014; 290:338-49. [PMID: 25411248 DOI: 10.1074/jbc.m114.597260] [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: 01/12/2023] Open
Abstract
Glomerular podocytes are highly specialized terminally differentiated cells that act as a filtration barrier in the kidney. Mutations in the actin-binding protein, α-actinin 4 (ACTN4), are linked to focal segmental glomerulosclerosis (FSGS), a chronic kidney disease characterized by proteinuria. Aberrant activation of NF-κB pathway in podocytes is implicated in glomerular diseases including proteinuria. We demonstrate here that stable knockdown of ACTN4 in podocytes significantly reduces TNFα-mediated induction of NF-κB target genes, including IL-1β and NPHS1, and activation of an NF-κB-driven reporter without interfering with p65 nuclear translocation. Overexpression of ACTN4 and an actin binding-defective variant increases the reporter activity. In contrast, an FSGS-linked ACTN4 mutant, K255E, which has increased actin binding activity and is predominantly cytoplasmic, fails to potentiate NF-κB activity. Mechanistically, IκBα blocks the association of ACTN4 and p65 in the cytosol. In response to TNFα, both NF-κB subunits p65 and p50 translocate to the nucleus, where they bind and recruit ACTN4 to their targeted promoters, IL-1β and IL-8. Taken together, our data identify ACTN4 as a novel coactivator for NF-κB transcription factors in podocytes. Importantly, this nuclear function of ACTN4 is independent of its actin binding activity in the cytoplasm.
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Affiliation(s)
| | | | | | - Leslie A Bruggeman
- Rammelkamp Center for Education and Research and Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Hung-Ying Kao
- From the Department of Biochemistry, Case Comprehensive Cancer Center, and
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Sedic M, Gethings LA, Vissers JPC, Shockcor JP, McDonald S, Vasieva O, Lemac M, Langridge JI, Batinić D, Pavelić SK. Label-free mass spectrometric profiling of urinary proteins and metabolites from paediatric idiopathic nephrotic syndrome. Biochem Biophys Res Commun 2014; 452:21-6. [PMID: 25150443 DOI: 10.1016/j.bbrc.2014.08.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 08/04/2014] [Indexed: 01/20/2023]
Abstract
Idiopathic nephrotic syndrome (INS) is caused by renal diseases that increase the permeability of the glomerular filtration barrier without evidence of a specific systemic cause. The aim of the present work was to reveal inherent molecular features of INS in children using combined urinary proteomics and metabolomics profiling. In this study, label-free mass spectrometric analysis of urinary proteins and small molecule metabolites was carried out in 12 patients with INS versus 12 sex- and age-matched control subjects with normal renal function. Integration and biological interpretation of obtained results were carried out by Ingenuity IPA software. Validation of obtained proteomics data was carried out by Western blot method. Proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000765. This study indicates for the first time that paediatric INS is associated with up-regulation of afamin, hydroxyphenylacetate and uridine, and concomitant down-regulation in glutamine and phenylalanine levels, and many of these molecular species were previously shown to be involved in oxidative stress. Further studies in larger patient population are underway to investigate the role of oxidative stress in renal injury in paediatric INS.
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Affiliation(s)
- Mirela Sedic
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Lee A Gethings
- Waters Corporation, MS Technologies, Manchester, United Kingdom
| | | | | | | | - Olga Vasieva
- Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, United Kingdom
| | - Maja Lemac
- Division of Nephrology, Department of Pediatrics, Zagreb University Hospital Centre, Zagreb, Croatia
| | | | - Danica Batinić
- Division of Nephrology, Department of Pediatrics, Zagreb University Hospital Centre, Zagreb, Croatia
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Wing MR, Ramezani A, Gill HS, Devaney JM, Raj DS. Epigenetics of progression of chronic kidney disease: fact or fantasy? Semin Nephrol 2014; 33:363-74. [PMID: 24011578 DOI: 10.1016/j.semnephrol.2013.05.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Epigenetic modifications are important in the normal functioning of the cell, from regulating dynamic expression of essential genes and associated proteins to repressing those that are unneeded. Epigenetic changes are essential for development and functioning of the kidney, and aberrant methylation, histone modifications, and expression of microRNA could lead to chronic kidney disease (CKD). Here, epigenetic modifications modulate transforming growth factor β signaling, inflammation, profibrotic genes, and the epithelial-to-mesenchymal transition, promoting renal fibrosis and progression of CKD. Identification of these epigenetic changes is important because they are potentially reversible and may serve as therapeutic targets in the future to prevent subsequent renal fibrosis and CKD. In this review we discuss the different types of epigenetic control, methods to study epigenetic modifications, and how epigenetics promotes progression of CKD.
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Affiliation(s)
- Maria R Wing
- Division of Renal Disease and Hypertension, The George Washington University, Washington, DC
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Abstract
Complement activation and recruitment of inflammatory leukocytes is an important defense mechanism against bacterial infection. However, complement also can mediate cellular injury and contribute to the pathogenesis of various diseases. With the appreciation that the C5b-9 membrane attack complex can injure cells in the absence of leukocytes, a role for the terminal complement pathway in inducing cell injury and kidney disease was shown in several experimental models, including the rat passive Heymann nephritis model of human membranous nephropathy. In podocytes, sublytic C5b-9 activates a variety of downstream pathways including protein kinases, lipid metabolism, reactive oxygen species, growth factors/gene transcription, endoplasmic reticulum stress, and the ubiquitin-proteasome system, and it impacts the integrity of the cytoskeleton and slit diaphragm proteins. C5b-9 also injures other kidney cells, including mesangial, glomerular endothelial, and tubular epithelial cells, and it contributes to the pathogenesis of mesangial-proliferative glomerulonephritis, thrombotic microangiopathy, and acute kidney injury. Conversely, certain C5b-9 signals limit complement-induced injury, or promote recovery of cells. In addition to C5b-9, complement cleavage products, such as C5a and C1q, can injure kidney cells. Thus, the complement system contributes to various kidney pathologies by causing cellular damage in both an inflammation-dependent and inflammation-independent manner.
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Affiliation(s)
- Tomoko Takano
- Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
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34
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Lin CL, Lee PH, Hsu YC, Lei CC, Ko JY, Chuang PC, Huang YT, Wang SY, Wu SL, Chen YS, Chiang WC, Reiser J, Wang FS. MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction. J Am Soc Nephrol 2014; 25:1698-709. [PMID: 24578127 DOI: 10.1681/asn.2013050527] [Citation(s) in RCA: 151] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.
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Affiliation(s)
- Chun-Liang Lin
- Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; School of Traditional Chinese Medicine and
| | - Pei-Hsien Lee
- Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yung-Chien Hsu
- Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chen-Chou Lei
- Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Jih-Yang Ko
- Departments of Orthopedic Surgery and Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | | | | | | | | | | | - Wen-Chih Chiang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jochen Reiser
- Department of Medicine, Rush University Medical Center, Chicago, Illinois; and
| | - Feng-Sheng Wang
- Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Medical Research and Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, TaoYuan, Taiwan
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Constitutional Nephrin Deficiency in Conditionally Immortalized Human Podocytes Induced Epithelial-Mesenchymal Transition, Supported by β-Catenin/NF-kappa B Activation: A Consequence of Cell Junction Impairment? Int J Nephrol 2013; 2013:457490. [PMID: 24392227 PMCID: PMC3874297 DOI: 10.1155/2013/457490] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/11/2013] [Indexed: 01/08/2023] Open
Abstract
The kidney glomerular podocytes are the cellular target of many chronic nephropathies both determined and acquired genetically. Mutations that affected the expression and/or the function of nephrin, a key component of the slit-diaphragm, are often causes of these pathologies. Recent findings showed that murine podocytes could undergo epithelial-mesenchymal transformation (EMT), suggesting new hypotheses about the pathogenesis of glomerular fibrosis. Here, we show that also human podocytes can undergo EMT, but more importantly nephrin ablation itself can trigger this phenotypic transformation. In fact, a model of human podocyte with engineered nephrin deficiency constitutionally expressed high levels of α-SMA, vimentin, fibronectin, and other hallmarks of EMT. Since it is known that cell contact abrogation is one of the triggers of EMT, we reasoned that nephrin loss could account for such cell junction disruption and cause the EMT. Therefore, we demonstrated that also normal podocytes could spontaneously undergo EMT if grown in Ca2+-free medium, which is known to impair cell contacts. The analysis of the main intracellular signal transduction pathways evidenced some major anomalies consequent with the nephrin abrogation. The most intriguing was the activation of β-catenin pathway, which plays a critical role in podocyte ontogenesis as well as in the nephrin expression and EMT regulation. Also other important signaling proteins, like NF-κB, p53, and retinoblastoma protein (RB), showed important activity modifications. Interestingly, most of the above indicated signaling pathway alterations were again reproducible by cell junction rupture, induced by Ca2+ deprivation. Finally, immunofluorescence analysis on kidney sections of patients with NS of Finnish type confirmed the constitutive expression of α-SMA.
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36
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Functions of the podocyte proteins nephrin and Neph3 and the transcriptional regulation of their genes. Clin Sci (Lond) 2013; 126:315-28. [DOI: 10.1042/cs20130258] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nephrin and Neph-family proteins [Neph1–3 (nephrin-like 1–3)] belong to the immunoglobulin superfamily of cell-adhesion receptors and are expressed in the glomerular podocytes. Both nephrin and Neph-family members function in cell adhesion and signalling, and thus regulate the structure and function of podocytes and maintain normal glomerular ultrafiltration. The expression of nephrin and Neph3 is altered in human proteinuric diseases emphasizing the importance of studying the transcriptional regulation of the nephrin and Neph3 genes NPHS1 (nephrosis 1, congenital, Finnish type) and KIRREL2 (kin of IRRE-like 2) respectively. The nephrin and Neph3 genes form a bidirectional gene pair, and they share transcriptional regulatory mechanisms. In the present review, we summarize the current knowledge of the functions of nephrin and Neph-family proteins and transcription factors and agents that control nephrin and Neph3 gene expression.
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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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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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Abstract
Observations of hereditary glomerular disease support the contention that podocyte intercellular junction proteins are essential for junction formation and maintenance. Genetic deletion of most of these podocyte intercellular junction proteins results in foot process effacement and proteinuria. This review focuses on the current understanding of molecular mechanisms by which podocyte intercellular junction proteins such as the nephrin-neph1-podocin-receptor complex coordinate cytoskeletal dynamics and thus intercellular junction formation, maintenance, and injury-dependent remodeling.
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Zhou TB, Qin YH. The signaling pathways of LMX1B and its role in glomerulosclerosis. J Recept Signal Transduct Res 2012; 32:285-289. [PMID: 23046462 DOI: 10.3109/10799893.2012.727832] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
LMX1B, a developmental LIM-homeodomain transcription factor, is widely expressed in vertebrate embryos, and it takes part in the development of diverse structures such as limbs, kidneys, eyes, brains, etc. LMX1B contributes to transcriptional regulation of glomerular basement membrane (GBM) collagen expression by podocytes. The normal function of podocytes and the normal morphology of GBM are very important to maintain the healthy renal filtration barrier. Recent discoveries find that the LMX1B gene is pivotal in glomus development and it is implicated in the dysfunction of the podocytes. Here, we review the signal transduction pathways of LMX1B and its role in the pathogenesis of glomerulosclerosis.
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Affiliation(s)
- Tian-Biao Zhou
- Department of Pediatric Nephrology, The First Affiliated Hospital of GuangXi Medical University, NanNing 530021, GuangXi, China
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Brähler S, Ising C, Hagmann H, Rasmus M, Hoehne M, Kurschat C, Kisner T, Goebel H, Shankland S, Addicks K, Thaiss F, Schermer B, Pasparakis M, Benzing T, Brinkkoetter PT. Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. Am J Physiol Renal Physiol 2012; 303:F1473-85. [DOI: 10.1152/ajprenal.00031.2012] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-κB signaling is among the most important regulators of proinflammatory signaling. Its role in podocytes, the epithelial cells at the kidney filtration barrier, is poorly understood. Here, we inhibited NF-κB signaling in podocytes by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-specific NEMO-deficient mice (NEMOpko) were viable and did not show proteinuria or overt changes in kidney morphology. After induction of glomerulonephritis, both NEMOpkoand control mice developed significant proteinuria. However, NEMOpkomice recovered much faster, showing rapid remission of proteinuria and restoration of podocyte morphology. Interestingly, quantification of infiltrating macrophages, T-lymphocytes, and granulocytes at day 7 revealed no significant difference between wild-type and NEMOpko. To further investigate the underlying mechanisms, we created a stable NEMO knockdown mouse podocyte cell line. Again, no overt changes in morphology were observed. Translocation of NF-κB to the nucleus after stimulation with TNFα or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNFα or IL-1 was significantly reduced in NEMO-deficient podocytes and in glomerular samples obtained at day 7 after induction of nephrotoxic nephritis. Collectively, these results show that proinflammatory activity of NF-κB in podocytes aggravates proteinuria in experimental glomerulonephritis in mice. Based on these data, it may be speculated that immunosuppressive drugs may not only target professional immune cells but also podocytes directly to convey their beneficial effects in various types of glomerulonephritis.
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Affiliation(s)
- Sebastian Brähler
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Christina Ising
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Henning Hagmann
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Melanie Rasmus
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Martin Hoehne
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Christine Kurschat
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Tuelay Kisner
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Heike Goebel
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Stuart Shankland
- Division of Nephrology, University of Washington, Seattle, Washington
| | - Klaus Addicks
- Institute of Anatomy, University of Cologne, Cologne, Germany
| | - Friedrich Thaiss
- Department of Internal Medicine III, University Hospital, Hamburg-Eppendorf, Hamburg, Germany
| | - Bernhard Schermer
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Manolis Pasparakis
- Institute for Genetics, University of Cologne, Cologne, Germany; and
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Paul Thomas Brinkkoetter
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
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Bayliss G, Weinrauch LA, D'Elia JA. Pathophysiology of obesity-related renal dysfunction contributes to diabetic nephropathy. Curr Diab Rep 2012; 12:440-6. [PMID: 22638939 DOI: 10.1007/s11892-012-0288-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Recent studies have demonstrated the role of insulin resistance in renal injury related to obesity, with hyperfiltration leading to glomerulomegaly in a pattern similar to that found in diabetic nephropathy. Similarities in the histologic patterns of damage from obesity and diabetes point to overlapping mechanisms of injury. In this review, we will examine the hormonal mechanisms, signaling pathways and injury patterns in renal injury resulting from obesity and attempt to draw conclusions on the reasons for these similarities.
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Affiliation(s)
- George Bayliss
- Division of Kidney Diseases and Hypertension, Rhode Island and Miriam Hospitals, Providence, USA.
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Ory V, Fan Q, Hamdaoui N, Zhang SY, Desvaux D, Audard V, Candelier M, Noel LH, Lang P, Guellaën G, Pawlak A, Sahali D. c-mip down-regulates NF-κB activity and promotes apoptosis in podocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:2284-92. [PMID: 22507836 DOI: 10.1016/j.ajpath.2012.02.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Revised: 01/28/2012] [Accepted: 02/07/2012] [Indexed: 11/26/2022]
Abstract
The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-κB may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-κB has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-κB family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of RelA prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a close spatial relationship. These results suggest that alterations in NF-κB activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS.
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Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice. Kidney Int 2012; 82:292-303. [PMID: 22475818 PMCID: PMC3410252 DOI: 10.1038/ki.2012.83] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1–7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy.
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p62: a versatile multitasker takes on cancer. Trends Biochem Sci 2012; 37:230-6. [PMID: 22424619 DOI: 10.1016/j.tibs.2012.02.008] [Citation(s) in RCA: 199] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 02/15/2012] [Accepted: 02/21/2012] [Indexed: 11/24/2022]
Abstract
Since its initial discovery as an atypical protein kinase C (PKC)-interacting protein, p62 has emerged as a crucial molecule in a myriad of cellular functions. This multifunctional role of p62 is explained by its ability to interact with several key components of various signaling mechanisms. Not surprisingly, p62 is required for tumor transformation owing to its roles as a key molecule in nutrient sensing, as a regulator and substrate of autophagy, as an inducer of oxidative detoxifying proteins, and as a modulator of mitotic transit and genomic stability; all crucial events in the control of cell growth and cancer.
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Ristola M, Arpiainen S, Saleem MA, Holthöfer H, Lehtonen S. Transcription of nephrin-Neph3 gene pair is synergistically activated by WT1 and NF-κB and silenced by DNA methylation. Nephrol Dial Transplant 2011; 27:1737-45. [PMID: 21980157 DOI: 10.1093/ndt/gfr576] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Nephrin and Neph3 are homologous molecules expressed in the podocyte slit diaphragms that are essential for normal glomerular ultrafiltration. Nephrin and Neph3 genes form a bidirectional gene pair suggesting that they may share key features in their regulation. We investigated if nephrin and Neph3 genes have similar mechanisms in their transcriptional regulation focussing on transcription factor Wilms' tumour 1 (WT1) and nuclear factor-κB (NF-κB) and DNA methylation. METHODS Transcriptional regulation of nephrin and Neph3 by WT1 and NF-κB was analysed by overexpression studies, reporter gene assay and chromatin immunoprecipitation using A293 cells and cultured podocytes. The interaction between WT1 and NF-κB was studied by co-immunoprecipitation. The effect of NF-κB activator tumour necrosis factor-α (TNF-α) with or without NF-κB pathway inhibitor (BAY 11-7082) on nephrin and Neph3 messenger RNA (mRNA) expression and on cellular distribution of NF-κB was determined by quantitative polymerase chain reaction (PCR) and immunostaining, respectively. The role of DNA methylation in regulating nephrin and Neph3 genes was studied by demethylating agent (5-aza-2'-deoxycytidine) treatment and quantitative PCR. RESULTS WT1 and NF-κB interact with nephrin and Neph3 promoter and cooperatively regulate nephrin and Neph3. The cooperation was further supported by the physical interaction between WT1 and NF-κB. TNF-α increased nephrin and Neph3 mRNA expression and this effect was mediated by NF-κB. Furthermore, DNA methylation played a role in silencing nephrin and Neph3 expression in a cell-type and differentiation stage-dependent manner. CONCLUSION These results provide novel insights into the transcriptional regulation of nephrin and Neph3 genes and indicate that nephrin and Neph3 share the same mechanisms in their regulation.
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Affiliation(s)
- Mervi Ristola
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland
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Kim J, Sohn E, Kim CS, Jo K, Kim JS. The role of high-mobility group box-1 protein in the development of diabetic nephropathy. Am J Nephrol 2011; 33:524-9. [PMID: 21606643 DOI: 10.1159/000327992] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 03/29/2011] [Indexed: 01/13/2023]
Abstract
BACKGROUND/AIMS The purpose of the experiment reported here was to assess the involvement of high-mobility group box-1 (HMGB1), receptor for advanced glycation end products (RAGE) and nuclear factor (NF)-κB signaling pathway in the development of rat diabetic nephropathy. METHODS Diabetes was induced by intraperitoneal streptozotocin injection in 7-week-old male rats. At 20 weeks of age, renal expression of HMGB1 was detected by immunohistochemistry. The expression of RAGE and NF-κB activity was studied by Western blot and electrophoretic mobility shift assay in renal tissues of normoglycemic and diabetic rats, respectively. RESULTS HMGB1 was highly expressed in both the cytoplasmic and nuclear patterns in diabetic renal glomerular cells and tubular epithelial cells, although in normal rats, HMGB1 was expressed only in the cell nuclei. The expression of RAGE, a potential receptor for HMGB1, and NF-κB activity were also greater in diabetic than in normal rats. Moreover, diabetes increased the binding of NF-κB to the RAGE promoter. CONCLUSION These findings suggest that hyperglycemia-induced HMGB1 release may induce the renal injury in diabetic rats, and that the pathogenic role of HMGB1 might be dependent on RAGE and through activation of NF-κB.
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Affiliation(s)
- Junghyun Kim
- Diabetic Complications Research Center, Division of Traditional Korean Medicine Integrated Research, Korea Institute of Oriental Medicine, Daejeon, South Korea
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D'Elia JA, Bayliss G, Roshan B, Maski M, Gleason RE, Weinrauch LA. Diabetic microvascular complications: possible targets for improved macrovascular outcomes. Int J Nephrol Renovasc Dis 2010; 4:1-15. [PMID: 21694944 PMCID: PMC3108788 DOI: 10.2147/ijnrd.s14716] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Indexed: 12/31/2022] Open
Abstract
The results of recent outcome trials challenge hypotheses that tight control of both glycohemoglobin and blood pressure diminishes macrovascular events and survival among type 2 diabetic patients. Relevant questions exist regarding the adequacy of glycohemoglobin alone as a measure of diabetes control. Are we ignoring mechanisms of vasculotoxicity (profibrosis, altered angiogenesis, hypertrophy, hyperplasia, and endothelial injury) inherent in current antihyperglycemic medications? Is the polypharmacy for lowering cholesterol, triglyceride, glucose, and systolic blood pressure producing drug interactions that are too complex to be clinically identified? We review angiotensin-aldosterone mechanisms of tissue injury that magnify microvascular damage caused by hyperglycemia and hypertension. Many studies describe interruption of these mechanisms, without hemodynamic consequence, in the preservation of function in type 1 diabetes. Possible interactions between the renin-angiotensin-aldosterone system and physiologic glycemic control (through pulsatile insulin release) suggest opportunities for further clinical investigation.
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Affiliation(s)
- John A D'Elia
- Renal Unit, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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