SIRT3 Protects Against Acute Kidney Injury via AMPK/mTOR-Regulated Autophagy

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.

Autophagy Function and Regulation in Kidney Disease

“…Furthermore, metformin [98] and neferine [99], which enhance autophagy via the AMPK/mTOR pathway, ameliorate cisplatin nephrotoxicity. In a sepsis model of cecal ligation and puncture, nicotinamide adenine dinucleotide NAD-dependent protein deacetylase SIRT3, a member of the mammalian sirtuin family of proteins, provided protection from sepsis-induced AKI through AMPK/mTOR-regulated autophagy [100]. In adriamycin-treated calcium-independent phospholipase A2 (iPLA2)γ knockout (KO) mice, both AMPK activation and autophagy were increased compared with treated control mice [101].…”

Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways

“…In a sepsis AKI model, SIRT3 was shown to have a protective effect on renal mitochondrial injury by reducing the production of ROS, and decreasing the release of IL-1β and IL-18 (Zhao et al, 2016). Overexpressing of SIRT3 promoted the autophagy and reduced the inflammasomes which are assembling in kidney injury caused by sepsis (Zhao et al, 2018). The use of cisplatin is often limited by the presence of AKI during chemotherapy (Huang et al, 2019).…”

“…Research shows that cisplatin may inhibit autophagy and activate NLRP3 leading to the kidney injury (Qu et al, 2018). However, SIRT3 can protect from the AKI caused by cisplatin by inducing autophagy (Zhao et al, 2018). Moreover, Astragaloside IV can protect from cisplatin-induced kidney injury by inducing the autophagy and suppressing the NF-kB signal pathway, thereby down-regulating the expression of NLRP3 inflammasome (Qu et al, 2019).…”

Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3

“…Previous reports have indicated that SIRT3 activation has antioxidative and anti-inflammatory effects. 11 , 12 In this study, we therefore used the SIRT3-activating compound honokiol (HKL) to explore the role of SIRT3 in radioprotection. HKL, also known as 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol, is a phenolic compound isolated from Magnolia grandiflora that has various properties, 13 including neuroprotective effects.…”