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

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.

Sun M ，Li J ，Mao L ，Wu J ，Deng Z ，He M ，An S ，Zeng Z ，Huang Q ，Chen Z ... -  《Frontiers in Immunology》

SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation.

Deng Z ，Sun M ，Wu J ，Fang H ，Cai S ，An S ，Huang Q ，Chen Z ，Wu C ，Zhou Z ，Hu H ，Zeng Z ... -  《Cell Death & Disease》

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model.

Xu S ，Gao Y ，Zhang Q ，Wei S ，Chen Z ，Dai X ，Zeng Z ，Zhao KS ... -  《-》

SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury.

Wei S ，Gao Y ，Dai X ，Fu W ，Cai S ，Fang H ，Zeng Z ，Chen Z ... -  《-》

SIRTUIN 5 ALLEVIATES EXCESSIVE MITOCHONDRIAL FISSION VIA DESUCCINYLATION OF ATPASE INHIBITORY FACTOR 1 IN SEPSIS-INDUCED ACUTE KIDNEY INJURY.

Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear. In this study, SAKI was modeled in mice through cecal ligation and puncture, and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout exhibited shortened survival times and elevated levels of renal injury compared to wild-type mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1. In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.

Li J ，Yao Y ，Lei X ，Bao J ，An S ，Hu H ，Sha T ，Huang Q ，Li T ，Zeng Z ，Wang X ，Cai S ... -  《-》