Open AccessmiR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury
Author(s) -
Yan Yu,
Zhigui Ma,
Jiefu Zhu,
Mengru Zeng,
Hong Liu,
Zheng Dong
Publication year - 2020
Publication title -
american journal of physiology. renal physiology./american journal of physiology. renal physiology
Language(s) - English
Resource type - Journals
eISSN - 1931-857X
pISSN - 1522-1466
DOI - 10.1152/ajprenal.00567.2019
Subject(s) - mfn2 , acute kidney injury , mitochondrial fusion , apoptosis , renal ischemia , kidney , ischemia , medicine , mitochondrial permeability transition pore , cancer research , downregulation and upregulation , mitochondrion , programmed cell death , fragmentation (computing) , microbiology and biotechnology , biology , reperfusion injury , mitochondrial dna , biochemistry , gene , ecology
Disruption of mitochondrial dynamics is an important pathogenic event in both acute and chronic kidney diseases, but the underlying mechanism remains poorly understood. Here, we report the regulation of mitofusin-2 (Mfn2; a key mitochondrial fusion protein) by microRNA-214 (miR-214) in renal ischemia-reperfusion that contributes to mitochondrial fragmentation, renal tubular cell death, and ischemic acute kidney injury (AKI). miR-214 was induced, whereas Mfn2 expression was decreased, in mouse ischemic AKI and cultured rat kidney proximal tubular cells (RPTCs) following ATP depletion treatment. Overexpression of miR-214 decreased Mfn2. Conversely, inhibition of miR-214 with anti-miR-214 prevented Mfn2 downregulation in RPTCs following ATP depletion. Anti-miR-214 further ameliorated mitochondrial fragmentation and apoptosis, whereas overexpression of miR-214 increased apoptosis, in ATP-depleted RPTCs. To test regulation in vivo, we established a mouse model with miR-214 specifically deleted from kidney proximal tubular cells (PT- miR-214 -/- ). Compared with wild-type mice, PT- miR-214 -/- mice had less severe tissue damage, fewer apoptotic cells, and better renal function after ischemic AKI. miR-214 induction in ischemic AKI was suppressed in PT- miR-214 -/- mice, accompanied by partial preservation of Mfn2 in kidneys. These results unveil the miR-214/Mfn2 axis that contributes to the disruption of mitochondrial dynamics and tubular cell death in ischemic AKI, offering new therapeutic targets.