Abstract
Acute kidney injury (AKI), which involves the loss of kidney function caused by damage to renal tubular cells, is an important public health concern. We previously showed that sirtuin (SIRT)3 protects the kidneys against mitochondrial damage by inhibiting the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, attenuating oxidative stress, and downregulating proinflammatory cytokines. In this article, we investigated the role of autophagy, mediated by a mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), in the protective effect of SIRT3, against sepsis-induced AKI, in a mouse model of cecal ligation and puncture (CLP). The AKI in CLP mice was associated with the upregulation of autophagy markers; this effect was abolished in SIRT3− mice in parallel with the downregulation of phospho (p)-AMPK and the upregulation of p-mTOR. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) or AMPK inhibitor compound isotonic saline (C), exacerbated AKI. SIRT3 overexpression promoted autophagy, upregulated p-AMPK and downregulated p-mTOR in CLP mice, attenuating sepsis-induced AKI, tubular cell apoptosis, and inflammatory cytokine accumulation in the kidneys. The blockage of autophagy induction largely abolished the protective effect of SIRT3 in sepsis-induced AKI. These findings indicate that SIRT3 protects against CLP-induced AKI by inducing autophagy through regulation of the AMPK/mTOR pathway.
Highlights
Acute kidney injury (AKI) is a loss of kidney function, with mixed etiology, including sepsis, ischemia, and nephrotoxicity (Makris and Spanou, 2016)
The cecal ligation and puncture (CLP) increased the levels of Blood urea nitrogen (BUN) and creatinine in WT mice, and this increase was significantly exacerbated in SIRT3−/− mice, which showed a twofold increase in the BUN and creatinine levels compared with the WT CLP mice (Figures 1B,C)
These results suggest that the protective effect of SIRT3 involves regulation of autophagy
Summary
Acute kidney injury (AKI) is a loss of kidney function, with mixed etiology, including sepsis, ischemia, and nephrotoxicity (Makris and Spanou, 2016). AKI is an important public health concern and acute renal failure occurs in approximately 17% of patients in intensive care units (ICUs), of whom, 50% develop renal failure during hospitalization (Clermont et al, 2002). Mitochondrial injury is a hallmark of AKI, and mitochondrial function is partly regulated by sirtuins (SIRTs), a conserved family of nictotinamide adenine dinucleotide (NAD+)-dependent deacetylases, involved in several processes, such as stress response, metabolism, development, and longevity (Haigis and Sinclair, 2010). SIRT3 is a potent deacetylase, expressed in humans as an enzymatically inactive 44-kDa protein with an N-terminal mitochondrial targeting sequence. SIRT3 is proteolytically processed to a mature 28-kDa active enzyme that functions as a positive regulator
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