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Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure

ABSTRACT: Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure

PROVIDER: PRJNA418148 | ENA |

REPOSITORIES: ENA

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Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure

Project description:Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2∆podocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2∆podocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2∆podocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)—unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2∆podocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.

2020-03-21 | GSE106828 | GEO

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

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Podocyte degradomics - N-Degradomic Analysis Reveals a Proteolytic Network Processing the Podocyte Cytoskeleton

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2017-07-20 | PXD005139 | Pride

Human podocyte cell culture degradomics

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Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

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Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis

Project description:Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis

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Anti-nephrin autoantibodies in minimal change disease and focal segmental glomerulosclerosis (proteomics)

Project description:Background: Minimal change disease (MCD) and focal-segmental glomerulosclerosis (FSGS) are immune-mediated glomerular diseases manifesting as nephrotic syndrome. Autoantibodies against the podocyte slit diaphragm protein nephrin were recently identified in a subset of patients with minimal change disease, but their clinical and pathophysiological significance is largely unknown. Methods: Using immunoprecipitation assays, we performed a blinded screening for anti-nephrin antibodies in diagnostic and follow-up serum samples from adult patients with biopsy-proven MCD, FSGS, IgA nephropathy, and membranous nephropathy in comparison to healthy controls in two independent patient cohorts from Hamburg, Germany, and Bari, Italy. We further established a mouse model of anti-nephrin antibody-induced disease by active immunization using the recombinant murine nephrin ectodomain. Results: Anti-nephrin autoantibodies were detected in 50 of 110 (45%) patients with MCD, 8 of 107 (7%) patients with FSGS, 1 of 50 (2%) patients with membranous nephropathy, 0 of 48 (0%) patients with IgA nephropathy, and 0 of 67 (0%) healthy individuals. During follow-up, presence, and absence of anti-nephrin autoantibodies in patients with MCD and FSGS strongly correlated with active disease and remission, respectively. Immunization of mice induced anti-nephrin autoantibody formation and a highly dynamic phenotype with severe nephrotic syndrome and the histological features of MCD. Mechanistically, anti-nephrin autoantibodies induced nephrin phosphorylation at Tyr1191, cytoskeletal rearrangement, and downregulation of key podocyte proteins. Conclusion: Anti-nephrin antibodies are a valuable biomarker of disease activity in patients with MCD and FSGS, and binding of anti-nephrin antibodies at the podocyte slit diaphragm induces MCD with nephrotic syndrome.

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