p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

被引:127
作者
Sun, Maomao [1 ,2 ]
Li, Jiaxin [1 ,2 ]
Mao, Liangfeng [1 ,2 ]
Wu, Jie [1 ]
Deng, Zhiya [1 ]
He, Man [1 ]
An, Sheng [1 ]
Zeng, Zhenhua [1 ,2 ]
Huang, Qiaobing [1 ,2 ]
Chen, Zhongqing [1 ,2 ]
机构
[1] Southern Med Univ, Nanfang Hosp, Dept Crit Care Med, Guangzhou, Guangdong, Peoples R China
[2] Southern Med Univ, Sch Basic Med Sci, Guangdong Prov Key Lab Shock & Microcirculat, Guangzhou, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
sepsis; acute kidney injury; autophagy; p53; deacetylation; MOUSE MODEL; INFLAMMATION; DYSFUNCTION; QUERCETIN; MITOPHAGY; PROTECTS; SURVIVAL; STRESS; CELLS; MICE;
D O I
10.3389/fimmu.2021.685523
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Recent studies have shown that autophagy upregulation can attenuate sepsis-induced acute kidney injury (SAKI). The tumor suppressor p53 has emerged as an autophagy regulator in various forms of acute kidney injury (AKI). Our previous studies showed that p53 acetylation exacerbated hemorrhagic shock-induced AKI and lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. However, the role of p53-regulated autophagy in SAKI has not been examined and requires clarification. In this study, we observed the dynamic changes of autophagy in renal tubular epithelial cells (RTECs) and verified the protective effects of autophagy activation on SAKI. We also examined the changes in the protein expression, intracellular distribution (nuclear and cytoplasmic), and acetylation/deacetylation levels of p53 during SAKI following cecal ligation and puncture (CLP) or LPS treatment in mice and in a LPS-challenged human RTEC cell line (HK-2 cells). After sepsis stimulation, the autophagy levels of RTECs increased temporarily, followed by a sharp decrease. Autophagy inhibition was accompanied by an increased renal tubular injury score. By contrast, autophagy agonists could reduce renal tubular damage following sepsis. Surprisingly, the expression of p53 protein in both the renal cortex and HK-2 cells did not significantly change following sepsis stimulation. However, the translocation of p53 from the nucleus to the cytoplasm increased, and the acetylation of p53 was enhanced. In the mechanistic study, we found that the induction of p53 deacetylation, due to either the resveratrol/quercetin -induced activation of the deacetylase Sirtuin 1 (Sirt1) or the mutation of the acetylated lysine site in p53, promoted RTEC autophagy and alleviated SAKI. In addition, we found that acetylated p53 was easier to bind with Beclin1 and accelerated its ubiquitination-mediated degradation. Our study underscores the importance of deacetylated p53-mediated RTEC autophagy in future SAKI treatments.
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页数:17
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[1]   Acute kidney injury in sepsis [J].
Bellomo, Rinaldo ;
Kellum, John A. ;
Ronco, Claudio ;
Wald, Ron ;
Martensson, Johan ;
Maiden, Matthew ;
Bagshaw, Sean M. ;
Glassford, Neil J. ;
Lankadeva, Yugeesh ;
Vaara, Suvi T. ;
Schneider, Antoine .
INTENSIVE CARE MEDICINE, 2017, 43 (06) :816-828
[2]   Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury [J].
Cao, Jing-Yuan ;
Wang, Bin ;
Tang, Tao-Tao ;
Wen, Yi ;
Li, Zuo-Lin ;
Feng, Song-Tao ;
Wu, Min ;
Liu, Dan ;
Yin, Di ;
Ma, Kun-Ling ;
Tang, Ri-Ning ;
Wu, Qiu-Li ;
Lan, Hui-Yao ;
Lv, Lin-Li ;
Liu, Bi-Cheng .
THERANOSTICS, 2021, 11 (11) :5248-5266
[3]   Autophagy and aging -: The importance of maintaining "clean" cells [J].
Cuervo, Ana Maria ;
Bergamini, Ettore ;
Brunk, Ulf T. ;
Droege, Wulf ;
Ffrench, Martine ;
Terman, Alexei .
AUTOPHAGY, 2005, 1 (03) :131-140
[4]   Involvement of phosphatase and tensin homolog-induced putative kinase 1-Parkin-mediated mitophagy in septic acute kidney injury [J].
Dai, Xin-Gui ;
Xu, Wei ;
Li, Tao ;
Lu, Jia-Ying ;
Yang, Yang ;
Li, Qiong ;
Zeng, Zhen-Hua ;
Ai, Yu-Hang .
CHINESE MEDICAL JOURNAL, 2019, 132 (19) :2340-2347
[5]   SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation [J].
Deng, Zhiya ;
Sun, Maomao ;
Wu, Jie ;
Fang, Haihong ;
Cai, Shumin ;
An, Sheng ;
Huang, Qiaobing ;
Chen, Zhenfeng ;
Wu, Chenglun ;
Zhou, Ziwei ;
Hu, Haoran ;
Zeng, Zhenhua .
CELL DEATH & DISEASE, 2021, 12 (02)
[6]   The p53-Target Gene Puma Drives Neutrophil-Mediated Protection against Lethal Bacterial Sepsis [J].
Garrison, Sean P. ;
Thornton, Justin A. ;
Haecker, Hans ;
Webby, Richard ;
Rehg, Jerold E. ;
Parganas, Evan ;
Zambetti, Gerard P. ;
Tuomanen, Elaine I. .
PLOS PATHOGENS, 2010, 6 (12)
[7]   A UNIFIED THEORY OF SEPSIS- INDUCED ACUTE KIDNEY INJURY: INFLAMMATION, MICROCIRCULATORY DYSFUNCTION, BIOENERGETICS, AND THE TUBULAR CELL ADAPTATION TO INJURY [J].
Gomez, Hernando ;
Ince, Can ;
De Backer, Daniel ;
Pickkers, Peter ;
Payen, Didier ;
Hotchkiss, John ;
Kellum, John A. .
SHOCK, 2014, 41 (01) :3-11
[8]   Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist [J].
Han, Dong ;
Li, Xiang ;
Li, Shuang ;
Su, Tao ;
Fan, Li ;
Fan, Wen-Si ;
Qiao, Hong-Yu ;
Chen, Jiang-Wei ;
Fan, Miao-Miao ;
Li, Xiu-Juan ;
Wang, Ya-Bin ;
Ma, Sai ;
Qiu, Ya ;
Tian, Zu-Hong ;
Cao, Feng .
FREE RADICAL BIOLOGY AND MEDICINE, 2017, 113 :291-303
[9]   Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury [J].
Holthoff, Joseph H. ;
Wang, Zhen ;
Seely, Kathryn A. ;
Gokden, Neriman ;
Mayeux, Philip R. .
KIDNEY INTERNATIONAL, 2012, 81 (04) :370-378
[10]   Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes [J].
Hoshino, Atsushi ;
Ariyoshi, Makoto ;
Okawa, Yoshifumi ;
Kaimoto, Satoshi ;
Uchihashi, Motoki ;
Fukai, Kuniyoshi ;
Iwai-Kanai, Eri ;
Ikeda, Koji ;
Ueyama, Tomomi ;
Ogata, Takehiro ;
Matoba, Satoaki .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (08) :3116-3121