MicroRNA-489 induction by hypoxia-inducible factor-1 protects against ischemic kidney injury

Qingqing Wei, Yong Liu, Pengyuan Liu, Jielu Hao, Mingyu Liang, Qing Sheng Mi, Jian Kang Chen, Zheng Dong

Research output: Contribution to journalArticle

40 Scopus citations

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 ofmice 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-1a deficiency associated with diminished microRNA-489 induction in cultured rat proximal tubular cells subjectedtohypoxia andkidney tissues ofmice after renal ischemia-reperfusioninjury.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. Inmice, 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.

Original languageEnglish (US)
Pages (from-to)2784-2796
Number of pages13
JournalJournal of the American Society of Nephrology
Volume27
Issue number9
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Nephrology

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