title: MicroRNA-489 Induction by Hypoxia-Inducible Factor-1 Protects against Ischemic Kidney Injury.
abstract: MicroRNAs have been implicated in ischemic AKI. However, the specific microRNA species that regulates ischemic kidney injury remains unidentified. Our previous microarray analysis revealed microRNA-489 induction in kidneys of mice subjected to renal ischemia-reperfusion. In this study, we verified the induction of microRNA-489 during ischemic AKI in mice and further examined the underlying mechanisms. Hypoxia-inducible factor-1α deficiency associated with diminished microRNA-489 induction in cultured rat proximal tubular cells subjected to hypoxia and kidney tissues of mice after renal ischemia-reperfusion injury. Moreover, genomic analysis revealed that microRNA-489 is intronic in the calcitonin receptor gene, and chromatin immunoprecipitation assays showed increased binding of hypoxia-inducible factor-1 to a specific site in the calcitonin receptor gene promoter after hypoxia. Inhibition of microRNA-489 increased apoptosis in renal tubular cells after ATP depletion injury in vitro, whereas microRNA-489 mimics mediated protection. In mice, inhibition of microRNA-489 enhanced tubular cell death and ischemic AKI without significantly affecting tubular cell proliferation. Deep sequencing identified 417 mRNAs that were recruited to the RNA-induced silencing complex by microRNA-489. Of the identified mRNAs, 127 contain microRNA-489 targeting sites, and of those, 18 are involved in the cellular stress response, including the poly(ADP-ribose) polymerase 1 gene implicated in ischemic kidney injury. Sequence analysis and in vitro studies validated poly(ADP-ribose) polymerase 1 as a microRNA-489 target. Together, these results suggest that microRNA-489 is induced via hypoxia-inducible factor-1 during ischemic AKI to protect kidneys by targeting relevant genes.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; zdong@gru.edu 30912.qwei@gru.edu.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; Kidney Institute, Changzheng Hospital of Second Military Medical University, Shanghai, China;
authors.forename: Jielu
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Mingyu
authors.initials: M
authors.lastname: Liang
authors.affiliation: Kidney Institute, Changzheng Hospital of Second Military Medical University, Shanghai, China; Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, Michigan; and.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia;
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; The Second Xiangya Hospital, Central South University, Changsha, China zdong@gru.edu 30912.qwei@gru.edu.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D002478:Cells, Cultured; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D051381:Rats
chemical_list: D051793:Hypoxia-Inducible Factor 1; C570982:MIRN489 microRNA, mouse; D035683:MicroRNAs
keywords: acute renal failure; apoptosis; gene expression; hypoxia