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

Abstract

Our previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

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

“…We found that the expression of autophagy-related protein LC3II increased gradually and peaked at 8 h, returned to baseline by 24 h. In contrast, p62 (SQSTM1, a mediator of cargo selection and an autophagic substrate) expression reached the lowest levels at 8 h with LPS treatment (Supplementary Figures 1A-C), which was consistent with the autophagosomes analysis in CLP-induced septic mouse model. Similar changes of LC3II and p62 have been reported in CLP model in our previous study (15).…”

“…Different from the final result of cell death caused by apoptosis, activated autophagy plays a renal protective role by preventing apoptosis, preserving the mitochondrial functions, and maintaining the balance between the productions of proand anti-inflammatory cytokines (22). Our previous research has confirmed the above phenomena and verified that autophagy activation could reduce SAKI (15). The role of p53 in SAKI is rarely reported, although previous studies have explored the damaging role of p53 in bilateral renal ischemia-reperfusion induced AKI and cisplatin nephrotoxic AKI (27,28).…”

“…Sirt1 deacetylates both histones and other non-histone proteins (10). Our previous studies have demonstrated that Sirt1 can improve SAKI by deacetylating Beclin1, which mediates autophagy activation (15). The first non-histone target that was identified for Sirt1 activity was p53.…”

“…Two septic animal models, CLP-and LPSinduced septic mouse models, were used in present study. The chemical reagents with doses of 4 mg/kg Rapa, 20 mg/kg 3-MA, 25 mg/kg tenovin-6, 50 mg/kg CHQ, 30 mg/kg RSV and 25 mg/ kg QCT were intraperitoneally injected 2 h before CLP as required, respectively (12)(13)(14)(15). All these chemical reagents were first dissolved in DMSO, and then diluted with saline to reach the working concentration.…”

The Role and Mechanism of Histone Deacetylases in Acute Kidney Injury

“…SIRT1 can induce autophagy by directly deacetylating autophagy-related 5, 7, 8 genes ( Lee et al, 2008) , and forming deacetylated Atg5, Atg7, and Atg8. SIRT1 activation can also induce autophagy by promoting the deacetylation of Beclin1 at K430 and K437 ( Deng et al, 2021 ). Oxidative stress is closely associated with cisplatin-induced AKI; in cisplatin-induced AKI, kidney damage caused by cisplatin reduces the number and function of mitochondria and increases the production of ROS.…”