Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 317, Issue 5, Pages F1311-F1317Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00072.2019
Keywords
cyclophilin D; ischemic renal injury; membrane permeability transition pore; p53
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Funding
- National Natural Science Foundation [81770667, 81570609]
- Natural Science Foundation of Guangdong Province [2016A030313767, 2014A030313545]
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Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-Cypl) complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.
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