Role of FOXO1 in aldosterone-induced autophagy: A compensatory protective mechanism related to podocyte injury
2016
// Bin Wang 1 , Wei Ding 2 , Minmin Zhang 1 , Hongmei Li 3 , Honglei Guo 3 , Lilu Lin 3 , Jing Chen 1 , Yong Gu 1 1 Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China 2 Division of Nephrology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 3 Division of Nephrology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China Correspondence to: Yong Gu, email: yonggu@vip163.com Keywords: podocyte, aldosterone, autophagy, FOXO1, apoptosis Received: February 21, 2016 Accepted: April 16, 2016 Published: May 26, 2016 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.
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