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MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury. J Clin Invest 2018 12 03;128(12):5448-5464

Date

10/17/2018

Pubmed ID

30325740

Pubmed Central ID

PMC6264638

DOI

10.1172/JCI121859

Scopus ID

2-s2.0-85058349510   25 Citations

Abstract

The pathogenesis of ischemic diseases remains unclear. Here we demonstrate the induction of microRNA-668 (miR-668) in ischemic acute kidney injury (AKI) in human patients, mice, and renal tubular cells. The induction was HIF-1 dependent, as HIF-1 deficiency in cells and kidney proximal tubules attenuated miR-668 expression. We further identified a functional HIF-1 binding site in the miR-668 gene promoter. Anti-miR-668 increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-668 mimic was protective. Mechanistically, anti-miR-668 induced mitochondrial fragmentation, whereas miR-668 blocked mitochondrial fragmentation during hypoxia. We analyzed miR-668 target genes through immunoprecipitation of microRNA-induced silencing complexes followed by RNA deep sequencing and identified 124 protein-coding genes as likely targets of miR-668. Among these genes, only mitochondrial protein 18 kDa (MTP18) has been implicated in mitochondrial dynamics. In renal cells and mouse kidneys, miR-668 mimic suppressed MTP18, whereas anti-miR-668 increased MTP18 expression. Luciferase microRNA target reporter assay further verified MTP18 as a direct target of miR-668. In renal tubular cells, knockdown of MTP18 suppressed mitochondrial fragmentation and apoptosis. Together, the results suggest that miR-668 is induced via HIF-1 in ischemic AKI and that, upon induction, miR-668 represses MTP18 to preserve mitochondrial dynamics for renal tubular cell survival and kidney protection.

Author List

Wei Q, Sun H, Song S, Liu Y, Liu P, Livingston MJ, Wang J, Liang M, Mi QS, Huo Y, Nahman NS, Mei C, Dong Z

Authors

Mingyu Liang PhD Center Director, Professor in the Physiology department at Medical College of Wisconsin
Yong Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct 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
Apoptosis
Female
Humans
Hypoxia
Male
Membrane Proteins
Mice
Mice, Knockout
MicroRNAs
Mitochondria
Mitochondrial Dynamics
Mitochondrial Proteins
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d