title: Pharmacological targeting of GSK3β confers protection against podocytopathy and proteinuria by desensitizing mitochondrial permeability transition.
abstract: OBJECTIVE
  Mitochondrial dysfunction, triggered by mitochondria permeability transition (MPT), has been centrally implicated in the pathogenesis of podocytopathy and involves a multitude of cell signalling mechanisms, among which, glycogen synthase kinase (GSK) 3β has emerged as the integration point and plays a crucial role. This study aimed to examine the role of GSK3β in podocyte MPT and mitochondrial dysfunction.
  
  
  METHODS
  The regulatory effect of GSK3β on MPT was examined in differentiated podocytes in culture and in a murine model of adriamycin-induced podocytopathy using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a highly selective small-molecule inhibitor of GSK3β.
  
  
  RESULTS
  TDZD-8 therapy prominently ameliorated the proteinuria and glomerular sclerosis in mice with adriamycin nephropathy; this was associated with a correction of GSK3β overactivity in the glomerulus and attenuation of podocyte injuries, including foot process effacement and podocyte death. Consistently, in adriamycin-injured podocytes, TDZD-8 treatment counteracted GSK3β overactivity, improved cell viability and prevented death, concomitant with diminished oxidative stress, improved mitochondrial dysfunction and desensitized MPT. Mechanistically, a discrete pool of GSK3β was found in podocyte mitochondria, which interacted with and phosphorylated clyclophilin F, a key structural component of the MPT pore. TDZD-8 treatment prevented the GSK3β-controlled phosphorylation and activation of cyclophilin F, desensitized MPT and alleviated the damage to mitochondria in podocytes induced by adriamycin in vivo and in vitro.
  
  
  CONCLUSIONS
  Our findings suggest that pharmacological targeting of GSK3β could represent a promising and feasible therapeutic strategy for protecting podocytes against mitochondrial dysfunction induced by oxidative 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, RI, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Bao
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.forename: Ai
authors.initials: A
authors.lastname: Peng
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D004317:Doxorubicin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3