MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury. J Clin Invest 2018 Dec 03;128(12):5448-5464
Date
10/17/2018Pubmed ID
30325740Pubmed Central ID
PMC6264638DOI
10.1172/JCI121859Scopus ID
2-s2.0-85058349510 (requires institutional sign-in at Scopus site) 112 CitationsAbstract
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 ZMESH terms used to index this publication - Major topics in bold
Acute Kidney InjuryAnimals
Apoptosis
Female
Humans
Hypoxia
Male
Membrane Proteins
Mice
Mice, Knockout
MicroRNAs
Mitochondria
Mitochondrial Dynamics
Mitochondrial Proteins
