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MicroRNA-489 Induction by Hypoxia-Inducible Factor-1 Protects against Ischemic Kidney Injury. J Am Soc Nephrol 2016 09;27(9):2784-96

Date

03/16/2016

Pubmed ID

26975439

Pubmed Central ID

PMC5004659

DOI

10.1681/ASN.2015080870

Scopus ID

2-s2.0-85006261234   41 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 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.

Author List

Wei Q, Liu Y, Liu P, Hao J, Liang M, Mi QS, Chen JK, Dong Z

Authors

Mingyu Liang PhD Center Director, Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Yong Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acute Kidney Injury
Animals
Cells, Cultured
Hypoxia-Inducible Factor 1
Kidney Tubules
Mice
MicroRNAs
Rats
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d