Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6

Jielu Hao, QingQing Wei, Shuqin Mei, Lin Li, Yunchao Su, Changlin Mei, Zheng Dong

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Renal ischemia-reperfusion injury is a leading cause of acute kidney injury; the pathogenesis of which remains poorly understood and effective therapies are still lacking. Here we tested whether microRNAs, identified as critical regulators of cell health and disease, are involved in this process. We found that miR-17-5p was significantly up-regulated during renal ischemia-reperfusion injury in mice and during hypoxia in cultured renal tubular cells. In cultured cells, miR-17-5p directly inhibited the expression of death receptor 6 (DR6) and attenuated apoptosis during hypoxia. Blockade of miR-17-5p abolished the suppression of DR6 and facilitated caspase activation and apoptosis. In vivo, an miR-17-5p mimic suppressed DR6 expression and protected against renal ischemia-reperfusion injury. We further verified that miR-17-5p induction during renal ischemia-reperfusion injury was dependent on p53. Inhibition of p53 with pifithrin-α or a dominant-negative mutant led to the repression of miR-17-5p expression under hypoxia in vitro. Moreover, miR-17-5p induction during renal ischemia-reperfusion injury was attenuated in proximal tubule p53 knockout mice, supporting the role of p53 in miR-17-5p induction in vivo. Thus, p53/miR-17-5p/DR6 is a new protective pathway in renal ischemia-reperfusion injury and may be targeted for the prevention and treatment of ischemic acute kidney injury.

Original languageEnglish (US)
Pages (from-to)106-118
Number of pages13
JournalKidney International
Volume91
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • acute kidney injury
  • death receptor
  • ischemia-reperfusion injury
  • microRNA

ASJC Scopus subject areas

  • Nephrology

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