title: The redox sensitive glycogen synthase kinase 3β suppresses the self-protective antioxidant response in podocytes upon oxidative glomerular injury.
abstract: The redox sensitive glycogen synthase kinase (GSK) 3 has been recently implicated in the pathogenesis of proteinuric glomerulopathy. However, prior studies are less conclusive because they relied solely on chemical inhibitors of GSK3, which provide poor discrimination between the isoforms of GSK3 apart from potential off target activities. In murine kidneys, the β rather than the α isoform of GSK3 was predominantly expressed in glomeruli and distributed intensely in podocytes. By employing the doxycycline-activated Cre-loxP site specific gene targeting system, GSK3β was successfully knocked out (KO) selectively in podocytes in adult mice, resulting in a phenotype no different from control littermates. Electron microscopy of glomeruli in KO mice demonstrated more glycogen accumulation in podocytes but otherwise normal ultrastructures. Upon oxidative glomerular injury induced by protein overload, KO mice excreted significantly less albuminuria and had much attenuated podocytopathy and glomerular damage. The anti-proteinuric and glomerular protective effect was concomitant with diminished accumulation of reactive oxygen species in glomeruli in KO mice, which was likely secondary to a reinforced Nrf2 antioxidant response in podocytes. Collectively, our data suggest that GSK3β is dispensable for glomerular function and histology under normal circumstances but may serve as a therapeutic target for protecting from oxidative glomerular injuries.
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: 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: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015151:Immunoblotting; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010084:Oxidation-Reduction; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D006003:Glycogen; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Pathology Section; antioxidant defense; conditional gene knockout; glycogen; glycogen synthase kinase 3β; podocyte