title: The β 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 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 ablation of GSK3β 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 GSK3β 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, GSK3β knockout diminished ADR-induced NFκB RelA/p65 phosphorylation selectively at serine 467; suppressed de novo expression by podocytes of NFκB-dependent podocytopathic mediators, including B7-1, cathepsin L, and MCP-1; but barely affected the induction of NFκB target pro-survival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death were significantly attenuated in GSK3β 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 β isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.
authors.affiliation: Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Changbin
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Dworkin
authors.affiliation: Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ai
authors.initials: A
authors.lastname: Peng
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004318:Doxycycline / Q000008:administration & dosage / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007674:Kidney Diseases / Q000201:enzymology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000209:etiology; D016328:NF-kappa B / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D011507:Proteinuria / Q000201:enzymology*
chemical_list: D016328:NF-kappa B; D020033:Protein Isoforms; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004318:Doxycycline
keywords: adriamycin; glomerulopathy; glycogen synthase kinase 3β; inducible gene knockout; podocyte; proteinuria