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.
Highlights
Sepsis is associated with physiological, pathological and biochemical abnormalities induced by infection[1]
Dynamic changes in autophagy in an animal model of Sepsis-induced acute kidney injury (SAKI) First, we determined whether caecal ligation and puncture (CLP)-induced SAKI was successfully established in mice
Western blotting showed that the expression of the autophagyrelated proteins Beclin[1] and LC3 increased after CLP, gradually peaked at 8 h, and returned to baseline by 24 h (Fig. 1G–I)
Summary
Sepsis is associated with physiological, pathological and biochemical abnormalities induced by infection[1]. Sepsis-induced acute kidney injury (SAKI) is a common and severe complication in septic patients and often contributes to high morbidity and mortality[2]. SAKI survivors have an increased prevalence of chronic kidney disease[3]. There is no ideal therapy for SAKI and effective treatments are urgently needed. It is of priority to fully understand the pathogenesis of SAKI. Recent studies have confirmed that autophagy, a selfdegradative process in cells depending on lysosomes, exerts protective effects against SAKI4. Autophagy and its associated pathways are potential targets and therapeutic interventions for SAKI. In a murine model of SAKI, diminished autophagy leads to failed recovery of renal function[5]. Autophagy activation has a protective effect in SAKI6. Beclin[1], can form different complexes that are involved in autophagosome initiation and autolysosome maturation[7]
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