p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy.
p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy.
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p53 脱乙酰化通过促进自噬减轻脓毒症引起的急性肾损伤
DOI：
10.3389/fimmu.2021.685523
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发表时间：
2021
影响因子：
7.3
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Sun M;Li J;Mao L;Wu J;Deng Z;He M;An S;Zeng Z;Huang Q;Chen Z
最近的研究表明，自噬上调可以减轻脓毒症所致的急性肾损伤(SAKI)。肿瘤抑制基因P53在各种形式的急性肾损伤(AKI)中作为自噬调节因子出现。我们以前的研究表明，P53乙酰化加剧了失血性休克诱导的AKI和内毒素(LPS)诱导的内皮屏障功能障碍。然而，P53调控的自噬在SAKI中的作用还没有被研究过，需要澄清。在本研究中，我们观察了肾小管上皮细胞(RTECs)自噬的动态变化，验证了自噬激活对SAKI的保护作用。我们还检测了盲肠结扎穿孔(CLP)或脂多糖(LPS)处理的小鼠和人RTEC细胞株(HK-2细胞)SAKI过程中p53蛋白表达、细胞内分布(核内和胞浆)和乙酰化/去乙酰化水平的变化。在脓毒症刺激后，RTECs的自噬水平暂时增加，然后急剧下降。自噬抑制伴随着肾小管损伤评分的增加。相比之下，自噬激动剂可以减少脓毒症后的肾小管损伤。令人惊讶的是，在脓毒症刺激后，肾皮质和HK-2细胞中P53蛋白的表达没有明显变化。但P53从胞核到胞浆的易位增加，P53的乙酰化增强。在机制研究中，我们发现，由于白藜芦醇/栎素诱导的脱乙酰酶Sirt1(Sirt1)的激活或P53乙酰化赖氨酸位点的突变，P53脱乙酰基的诱导促进了RTEC的自噬，并减轻了SAKI。此外，我们发现乙酰化的p53更容易与Beclin1结合，并加速了其泛素化介导的降解。我们的研究强调了去乙酰化的p53介导的RTEC自噬在未来SAKI治疗中的重要性。
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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影响因子：
19.6
作者：
Kaushal GP;Shah SV
通讯作者：
Shah SV
影响因子：
13.6
作者：
Sutton, Timothy A.;Hato, Takashi;Dagher, Pierre C.
通讯作者：
Dagher, Pierre C.
DOI：
10.1152/ajplung.00043.2016
发表时间：
2016-12-01
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
--
作者：
Jiang Y;Zeng Y;Huang X;Qin Y;Luo W;Xiang S;Sooranna SR;Pinhu L
通讯作者：
Pinhu L
沉默信息调节器 1 信号传导减少会加剧脓毒症引起的心肌损伤并减轻肝脏 X 受体激动剂的保护作用
影响因子：
7.4
作者：
Han, Dong;Li, Xiang;Cao, Feng
通讯作者：
Cao, Feng
影响因子：
6.1
作者：
Dai, Xin-Gui;Xu, Wei;Ai, Yu-Hang
通讯作者：
Ai, Yu-Hang