| First Author | Li C | Year | 2016 |
| Journal | J Pathol | Volume | 239 |
| Issue | 1 | Pages | 23-35 |
| PubMed ID | 26876299 | Mgi Jnum | J:241100 |
| Mgi Id | MGI:5897727 | Doi | 10.1002/path.4692 |
| Citation | Li C, et al. (2016) The beta isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy. J Pathol 239(1):23-35 |
| abstractText | 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 beta isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3beta expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte-specific somatic ablation of GSK3beta 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 GSK3beta 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, GSK3beta knockout diminished ADR-induced NFkappaB RelA/p65 phosphorylation selectively at serine 467; suppressed de novo expression by podocytes of NFkappaB-dependent podocytopathic mediators, including B7-1, cathepsin L, and MCP-1; but barely affected the induction of NFkappaB target pro-survival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death were significantly attenuated in GSK3beta 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 beta isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways. |
