MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury

QingQing Wei, Haipeng Sun, Shuwei Song, Yong Liu, Pengyuan Liu, Man Jiang Livingston, Jianwen Wang, Mingyu Liang, Qing Sheng Mi, Yuqing Huo, Norris Stanley Nahman, Changlin Mei, Zheng Dong

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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.

Original languageEnglish (US)
Pages (from-to)5448-5464
Number of pages17
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Mitochondrial Dynamics
Mitochondrial Proteins
MicroRNAs
Acute Kidney Injury
Kidney
Apoptosis
Genes
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
Proximal Kidney Tubule
Luciferases
Immunoprecipitation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury. / Wei, QingQing; Sun, Haipeng; Song, Shuwei; Liu, Yong; Liu, Pengyuan; Livingston, Man Jiang; Wang, Jianwen; Liang, Mingyu; Mi, Qing Sheng; Huo, Yuqing; Nahman, Norris Stanley; Mei, Changlin; Dong, Zheng.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5448-5464.

Research output: Contribution to journalArticle

Wei, QingQing ; Sun, Haipeng ; Song, Shuwei ; Liu, Yong ; Liu, Pengyuan ; Livingston, Man Jiang ; Wang, Jianwen ; Liang, Mingyu ; Mi, Qing Sheng ; Huo, Yuqing ; Nahman, Norris Stanley ; Mei, Changlin ; Dong, Zheng. / MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5448-5464.
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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.",
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AU - Wei, QingQing

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AU - Song, Shuwei

AU - Liu, Yong

AU - Liu, Pengyuan

AU - Livingston, Man Jiang

AU - Wang, Jianwen

AU - Liang, Mingyu

AU - Mi, Qing Sheng

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AU - Nahman, Norris Stanley

AU - Mei, Changlin

AU - Dong, Zheng

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AB - 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.

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