title: Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury.
abstract: Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1α and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stress-induced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1α-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1α-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.
authors.affiliation: Dept. of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi Univ., Kohasu, Oko-cho, Nankoku 783-8505, Japan. terada@kochi-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishihara
authors.forename: Madoka
authors.initials: M
authors.lastname: Urushido
authors.forename: Kazu
authors.initials: K
authors.lastname: Hamada
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shimamura
authors.forename: Koji
authors.initials: K
authors.lastname: Ogata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Inoue
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Taro
authors.initials: T
authors.lastname: Horino
authors.forename: Mikiya
authors.initials: M
authors.lastname: Fujieda
authors.forename: Shimpei
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terada
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins; D063306:Mitophagy / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D000084622:Sestrins
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C505650:BNIP3 protein, rat; C583887:Sesn2 protein, rat; D000084622:Sestrins
keywords: Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2