P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

Huan Yang; Ruizhao Li; Li Zhang; Shu Zhang; Wei Dong; Yuanhan Chen; Weidong Wang; Chunling Li; Zhiming Ye; Xingchen Zhao; Zhilian Li; Yanhua Wu; Mengxi Zhang; Shuangxin Liu; Zheng Dong; Xinling Liang

doi:10.1152/ajprenal.00072.2019

P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

Huan Yang, Ruizhao Li, Li Zhang, Shu Zhang, Wei Dong, Yuanhan Chen, Weidong Wang, Chunling Li, Zhiming Ye, Xingchen Zhao, Zhilian Li, Yanhua Wu, Mengxi Zhang, Shuangxin Liu, Zheng Dong, Xinling Liang

Cellular Biology and Anatomy

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25 Scopus citations

Abstract

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-CypD 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.

Original language	English (US)
Pages (from-to)	F1311-F1317
Journal	American Journal of Physiology - Renal Physiology
Volume	317
Issue number	5
DOIs	https://doi.org/10.1152/ajprenal.00072.2019
State	Published - Nov 2019

Keywords

Cyclophilin D
Ischemic renal injury
Membrane permeability transition pore
P53

ASJC Scopus subject areas

Physiology
Urology

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10.1152/ajprenal.00072.2019

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Yang, H., Li, R., Zhang, L., Zhang, S., Dong, W., Chen, Y., Wang, W., Li, C., Ye, Z., Zhao, X., Li, Z., Wu, Y., Zhang, M., Liu, S., Dong, Z., & Liang, X. (2019). P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury. American Journal of Physiology - Renal Physiology, 317(5), F1311-F1317. https://doi.org/10.1152/ajprenal.00072.2019

Yang, H, Li, R, Zhang, L, Zhang, S, Dong, W, Chen, Y, Wang, W, Li, C, Ye, Z, Zhao, X, Li, Z, Wu, Y, Zhang, M, Liu, S, Dong, Z & Liang, X 2019, 'P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury', American Journal of Physiology - Renal Physiology, vol. 317, no. 5, pp. F1311-F1317. https://doi.org/10.1152/ajprenal.00072.2019

@article{a7b744b2328245be9c9826c42dcb5de2,

title = "P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury",

abstract = "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-CypD 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.",

keywords = "Cyclophilin D, Ischemic renal injury, Membrane permeability transition pore, P53",

author = "Huan Yang and Ruizhao Li and Li Zhang and Shu Zhang and Wei Dong and Yuanhan Chen and Weidong Wang and Chunling Li and Zhiming Ye and Xingchen Zhao and Zhilian Li and Yanhua Wu and Mengxi Zhang and Shuangxin Liu and Zheng Dong and Xinling Liang",

note = "Funding Information: This work was supported by National Natural Science Foundation Grants 81770667 and 81570609 and Natural Science Foundation of Guangdong Province Grants 2016A030313767 and 2014A030313545.*%blankline%* Funding Information: This work was supported by National Natural Science Foundation Grants 81770667 and 81570609 and Natural Science Foundation of Guangdong Province Grants 2016A030313767 and 2014A030313545. Publisher Copyright: {\textcopyright} 2019 American Physiological Society. All rights reserved.",

year = "2019",

month = nov,

doi = "10.1152/ajprenal.00072.2019",

language = "English (US)",

volume = "317",

pages = "F1311--F1317",

journal = "American Journal of Physiology - Renal Physiology",

issn = "1931-857X",

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TY - JOUR

T1 - P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

AU - Yang, Huan

AU - Li, Ruizhao

AU - Zhang, Li

AU - Zhang, Shu

AU - Dong, Wei

AU - Chen, Yuanhan

AU - Wang, Weidong

AU - Li, Chunling

AU - Ye, Zhiming

AU - Zhao, Xingchen

AU - Li, Zhilian

AU - Wu, Yanhua

AU - Zhang, Mengxi

AU - Liu, Shuangxin

AU - Dong, Zheng

AU - Liang, Xinling

N1 - Funding Information: This work was supported by National Natural Science Foundation Grants 81770667 and 81570609 and Natural Science Foundation of Guangdong Province Grants 2016A030313767 and 2014A030313545.*%blankline%* Funding Information: This work was supported by National Natural Science Foundation Grants 81770667 and 81570609 and Natural Science Foundation of Guangdong Province Grants 2016A030313767 and 2014A030313545. Publisher Copyright: © 2019 American Physiological Society. All rights reserved.

PY - 2019/11

Y1 - 2019/11

N2 - 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-CypD 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.

AB - 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-CypD 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.

KW - Cyclophilin D

KW - Ischemic renal injury

KW - Membrane permeability transition pore

KW - P53

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DO - 10.1152/ajprenal.00072.2019

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C2 - 31339772

AN - SCOPUS:85074676034

SN - 1931-857X

VL - 317

SP - F1311-F1317

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

IS - 5

ER -

P53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

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