title: Role of FOXO1 in aldosterone-induced autophagy: a compensatory protective mechanism related to podocyte injury.
abstract: This study was undertaken to elucidate whether and how autophagy was regulated in aldosterone (Aldo)-induced podocyte injury and to examine its role in this model both in vitro and in vivo. In cultured podocytes, Aldo increased autophagy flux as indicated by the enhanced expression of LC3-II/LC3-I and the reduction of p62. Autophagy induction with rapamycin (RP) provided a cytoprotective effect, and inhibition of autophagy with Atg7-specific siRNA, chloroquine (CQ) or 3-methyladenine (3-MA) worsened Aldo-induced podocyte injury by attenuating endoplasmic reticulum (ER) stress. Aldo inhibited Akt phosphorylation but increased the mammalian target of rapamycin (mTOR) signaling pathway; however, Aldo up-regulated the expression of FOXO1 and its downstream effector Rab7. Either knockdown of FOXO1 or Rab7 inhibited Aldo-induced autophagy. Additionally, an elevated level of P300-regulated acetylation of FOXO1 and the interaction of acetylated FOXO1 and Atg7 were also confirmed to be involved in regulating autophagy in Aldo-induced podocytes. Similar results were further confirmed in vivo. We propose that autophagy enhancement through enhancing of the FOXO1/Rab7 axis and post-translational modification of FOXO1 may represent a potential therapeutic strategy against podocyte injury by promoting autophagy.
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Guo
authors.affiliation: Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Lilu
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D050199:Podocytes / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000502:physiology; D000090802:rab7 GTP-Binding Proteins; D000071161:Forkhead Box Protein O1
chemical_list: D000450:Aldosterone; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; C000716466:rab7 GTP-binding proteins, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C546845:mTOR protein, rat
keywords: FOXO1; aldosterone; apoptosis; autophagy; podocyte