TY - JOUR
T1 - MicroRNA-489 induction by hypoxia-inducible factor-1 protects against ischemic kidney injury
AU - Wei, Qingqing
AU - Liu, Yong
AU - Liu, Pengyuan
AU - Hao, Jielu
AU - Liang, Mingyu
AU - Mi, Qing Sheng
AU - Chen, Jian Kang
AU - Dong, Zheng
N1 - Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2015080870
DO - 10.1681/ASN.2015080870
M3 - Article
C2 - 26975439
AN - SCOPUS:85006261234
SN - 1046-6673
VL - 27
SP - 2784
EP - 2796
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 9
ER -