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The ? isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy.

ABSTRACT: Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the ? isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3? expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte-specific somatic ablation of GSK3? in adult mice attenuated proteinuria and ameliorated podocyte injury and glomerular damage in experimental adriamycin (ADR) nephropathy. Mechanistically, actin cytoskeleton integrity in podocytes was largely preserved in GSK3? knockout mice following ADR insult, concomitant with a correction of podocyte hypermotility and lessened phosphorylation and activation of paxillin, a focal adhesion-associated adaptor protein. In addition, GSK3? knockout diminished ADR-induced NF?B RelA/p65 phosphorylation selectively at serine 467; suppressed de novo expression by podocytes of NF?B-dependent podocytopathic mediators, including B7-1, cathepsin L, and MCP-1; but barely affected the induction of NF?B target pro-survival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death were significantly attenuated in GSK3? knockout mice, associated with protection against podocyte mitochondrial damage and reduced phosphorylation and activation of cyclophilin F, a structural component of mitochondria permeability transition pores. Overall, our findings suggest that the ? isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.

SUBMITTER: Li C

PROVIDER: S-EPMC4833638 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy.

Li Changbin C Ge Yan Y Dworkin Lance L Peng Ai A Gong Rujun R

The Journal of pathology 20160316 1

Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the β isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3β expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte-specific somatic abla ...[more]

PMID: 26876299

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Project description:BackgroundGenetic mutations in α-actinin-4 (ACTN4)-an important actin crosslinking cytoskeletal protein that provides structural support for kidney podocytes-have been linked to proteinuric glomerulosclerosis in humans. However, the effect of post-translational modifications of ACTN4 on podocyte integrity and kidney function is not known.MethodsUsing mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation in vitro and in vivo. We conducted x-ray crystallography, F-actin binding and bundling assays, and immunofluorescence staining to evaluate F-actin alignment. Microfluidic organ-on-a-chip technology was used to assess for detachment of podocytes simultaneously exposed to fluid flow and cyclic strain. We then used CRISPR/Cas9 to generate mouse models and assessed for renal injury by measuring albuminuria and examining kidney histology. We also performed targeted mass spectrometry to determine whether high extracellular glucose or TGF-β levels increase phosphorylation of ACTN4.ResultsCompared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin in vitro. Phosphomimetic Actn4 mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. Moreover, we found that exposure to high extracellular glucose or TGF-β stimulates phosphorylation of ACTN4 at S159 in podocytes.ConclusionsThese findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.

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The ? isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy.

Publications

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy.

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