Dataset Information

Association of FOS-like antigen 1 promoter polymorphism with podocyte foot process effacement in immunoglobulin A nephropathy patients.

ABSTRACT: BACKGROUND:FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients. METHODS:We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and rs925255 for FOSL2) using direct sequencing in 198 IgAN patients and 290 control subjects. RESULTS:No SNPs were associated with IgAN; however, in the analysis of clinical phenotypes, we found that rs637571 of FOSL1 was associated with podocyte foot process effacement of IgAN in additive (CT vs. TT vs. CC, P = 0.0031, OR = 2.08, 95% CI = 1.27-3.40) and dominant models (CT/TT vs. CC, P = 0.0034, OR = 2.50, 95% CI = 1.35-4.64). The frequency of genotypes containing the T allele was increased in IgAN patients with podocyte foot process effacement, compared to those without podocyte foot process effacement. CONCLUSION:These results suggest that FOSL1 may be related to IgAN severity.

SUBMITTER: Park HJ

PROVIDER: S-EPMC6807477 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Association of FOS-like antigen 1 promoter polymorphism with podocyte foot process effacement in immunoglobulin A nephropathy patients.

Park Hae Jeong HJ Kim Jong Woo JW Cho Byoung-Soo BS Chung Joo-Ho JH

Journal of clinical laboratory analysis 20140320 5

<h4>Background</h4>FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients.<h4>Methods</h4>We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and r ...[more]

PMID: 24652774

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Project description:Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

Project description:BackgroundPrevious research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.MethodsWe conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped in vivo, podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting Srgap1. To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy; in situ proximity ligation assays were used to determine the subcellular localization of the small GTPase-activating protein SRGAP1. We performed functional analysis of CRISPR/Cas9-generated SRGAP1 knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics.ResultsWe demonstrated SRGAP1 localization to podocyte foot processes in vivo and to cellular protrusions in vitro. Srgap1fl/fl*Six2Cre but not Srgap1fl/fl*hNPHS2Cre knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of Srgap1 by hNPHS2Cre resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore, SRGAP1-knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery in vitro. Evaluation of a SRGAP1-dependent interactome revealed the involvement of SRGAP1 with protrusive and contractile actin networks. Analysis of glomerular biopsy specimens translated these findings toward human disease by displaying a pronounced redistribution of SRGAP1 in FSGS.ConclusionsSRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.

Dataset Information

Association of FOS-like antigen 1 promoter polymorphism with podocyte foot process effacement in immunoglobulin A nephropathy patients.

Publications

Association of FOS-like antigen 1 promoter polymorphism with podocyte foot process effacement in immunoglobulin A nephropathy patients.

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