Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21.
Delayed ischemic preconditioning effectively protects kidneys from ischemia-reperfusion injury but the mechanism underlying renal protection remains poorly understood. Here we examined the in vivo role of microRNA miR-21 in the renal protection conferred by delayed ischemic preconditioning in mice. A 15-min renal ischemic preconditioning significantly increased the expression of miR-21 by 4 h and substantially attenuated ischemia-reperfusion injury induced 4 days later. A locked nucleic acid-modified anti-miR-21 given at the time of ischemic preconditioning knocked down miR-21 and significantly exacerbated subsequent ischemia-reperfusion injury in the mouse kidney. Knockdown of miR-21 resulted in significant upregulation of programmed cell death protein 4, a proapoptotic target gene of miR-21, and substantially increased tubular cell apoptosis. Hypoxia-inducible factor-1α in the kidney was activated after ischemic preconditioning and blockade of its activity with a decoy abolished the upregulation of miR-21 in cultured human renal epithelial cells treated with the inducer cobalt chloride. In the absence of ischemic preconditioning, knockdown of miR-21 alone did not significantly affect ischemia-reperfusion injury in the mouse kidney. Thus, upregulation of miR-21 contributes to the protective effect of delayed ischemic preconditioning against subsequent renal ischemia-reperfusion injury.
Division of Nephrology, Shanghai Medical College, Fudan University, Zhongshan Hospital, Shanghai, PR China.
Xialian
X
Xu
Alison J
AJ
Kriegel
Yong
Y
Liu
Kristie
K
Usa
Domagoj
D
Mladinov
Hong
H
Liu
Yi
Y
Fang
Xiaoqiang
X
Ding
Mingyu
M
Liang
D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019194:Ischemic Preconditioning; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins