title: Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation.
abstract: Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19±3.86% of total glomeruli in knockouts vs. 0% in control littermates, n=12-36, P=0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92±11.961% of total glomeruli in knockouts vs. 0% in control littermates, n=4-7, P=0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Junhua
authors.initials: J
authors.lastname: Mao
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Jiangzhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Urology, 1st People's Hospital of Changzhou, Changzhou, China; and.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zhangxue
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China;
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China; State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; daichunsun@njmu.edu.cn.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000503:physiopathology; D002648:Child; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D011695:IgA Vasculitis / Q000503:physiopathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C514936:CXCR4 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D019718:Receptors, CXCR4; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: TORC1; crescent formation; parietal cell; podocyte