Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6.
Renal ischemia-reperfusion injury is a leading cause of acute kidney injury; the pathogenesis of which remains poorly understood and effective therapies are still lacking. Here we tested whether microRNAs, identified as critical regulators of cell health and disease, are involved in this process. We found that miR-17-5p was significantly up-regulated during renal ischemia-reperfusion injury in mice and during hypoxia in cultured renal tubular cells. In cultured cells, miR-17-5p directly inhibited the expression of death receptor 6 (DR6) and attenuated apoptosis during hypoxia. Blockade of miR-17-5p abolished the suppression of DR6 and facilitated caspase activation and apoptosis. In vivo, an miR-17-5p mimic suppressed DR6 expression and protected against renal ischemia-reperfusion injury. We further verified that miR-17-5p induction during renal ischemia-reperfusion injury was dependent on p53. Inhibition of p53 with pifithrin-α or a dominant-negative mutant led to the repression of miR-17-5p expression under hypoxia in vitro. Moreover, miR-17-5p induction during renal ischemia-reperfusion injury was attenuated in proximal tubule p53 knockout mice, supporting the role of p53 in miR-17-5p induction in vivo. Thus, p53/miR-17-5p/DR6 is a new protective pathway in renal ischemia-reperfusion injury and may be targeted for the prevention and treatment of ischemic acute kidney injury.
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
Jielu
J
Hao
Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
Qingqing
Q
Wei
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
Shuqin
S
Mei
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
Lin
L
Li
Department of Pharmacology and Toxicology, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
Yunchao
Y
Su
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: chlmei1954@126.com.
Changlin
C
Mei
Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA; Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: zdong@augusta.edu.
Zheng
Z
Dong
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D052160:Benzothiazoles; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D020169:Caspases
acute kidney injury; death receptor; ischemia-reperfusion injury; microRNA