title: Glycogen synthase kinase 3β orchestrates microtubule remodeling in compensatory glomerular adaptation to podocyte depletion.
abstract: Reminiscent of neural repair, following podocyte depletion, remnant-surviving podocytes exhibit a considerable adaptive capacity to expand and cover the denuded renal glomerular basement membrane. Microtubules, one of the principal cytoskeletal components of podocyte major processes, play a crucial role in podocyte morphogenesis and podocyte process outgrowth, branching, and elongation. Here, we demonstrated that the microtubule-associated proteins Tau and collapsin response mediator protein (CRMP) 2, key regulators of microtubule dynamics, were abundantly expressed by glomerular podocytes in vivo and in vitro, interacted with glycogen synthase kinase (GSK)3β, and served as its putative substrates. GSK3β overactivity induced by adriamycin injury or by a constitutively active mutant of GSK3β augmented phosphorylation of Tau and CRMP2, concomitant with microtubule depolymerization, cell body shrinkage, and shortening of podocyte processes. Conversely, inhibition of GSK3β by a dominant negative mutant or by lithium, a Food and Drug Administration-approved neuroprotective mood stabilizer, diminished Tau and CRMP2 phosphorylation, resulting in microtubule polymerization, podocyte expansion, and lengthening of podocyte processes. In a mouse model of adriamycin-induced podocyte depletion and nephropathy, delayed administration of a single low dose of lithium attenuated proteinuria and ameliorated progressive glomerulosclerosis despite no correction of podocytopenia. Mechanistically, lithium therapy obliterated GSK3β overactivity, mitigated phosphorylation of Tau and CRMP2, and enhanced microtubule polymerization and stabilization in glomeruli in adriamycin-injured kidneys, associated with elongation of podocyte major processes. Collectively, our findings suggest that the GSK3β-dictated podocyte microtubule dynamics might serve as a novel therapeutic target to reinforce the compensatory glomerular adaptation to podocyte loss.
authors.affiliation: From the National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China and the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xu
authors.affiliation: the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.affiliation: From the National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China and.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: the Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903 rujun_gong@Brown.edu.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002470:Cell Survival; D004317:Doxorubicin / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008094:Lithium / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000166:cytology*; D011507:Proteinuria / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D016875:tau Proteins; D004317:Doxorubicin; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Cytoskeleton; Glycogen Synthase Kinase 3β; Microtubule; Microtubule-associated Protein (MAP); Podocyte; Proteinuria; Tau Protein (Tau)