TY - JOUR
T1 - MiR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury
AU - Yan, Yu
AU - Ma, Zhengwei
AU - Zhu, Jiefu
AU - Zeng, Mengru
AU - Liu, Hong
AU - Dong, Zheng
N1 - Funding Information:
This work was supported in part by Department of Veterans Affairs Merit Review Award I01 BX000319 and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-058831 and DK-087843. Z. Dong is a recipient of the Senior Research Career Scientist award from the Department of Veterans Affairs.
Publisher Copyright:
© 2020 the American Physiological Society.
PY - 2020/4
Y1 - 2020/4
N2 - miR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury. Am J Physiol Renal Physiol 318: F878-F887, 2020. First published January 31, 2020; doi:10.1152/ajprenal. 00567.2019.-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 ATPdepleted 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.
AB - miR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury. Am J Physiol Renal Physiol 318: F878-F887, 2020. First published January 31, 2020; doi:10.1152/ajprenal. 00567.2019.-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 ATPdepleted 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.
KW - Ischemia-reperfusion
KW - Kidney
KW - Microrna-214
KW - Mitochondria
KW - Mitofusin
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U2 - 10.1152/AJPRENAL.00567.2019
DO - 10.1152/AJPRENAL.00567.2019
M3 - Article
C2 - 32003595
AN - SCOPUS:85082144799
SN - 1931-857X
VL - 318
SP - F878-F887
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4
ER -