Abstract
Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD+ dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18.
Highlights
Examined using a caecal ligation and puncture (CLP) model of sepsis-induced Acute kidney injury (AKI) in a Sirtuin 3 (SIRT3) knockout mouse model
Double immunofluorescence staining with SIRT3 and kidney injury molecule 1 (KIM-1) showed that KIM-1 was upregulated concomitant with the downregulation of SIRT3 in response to CLP (Fig. 1H)
The sirtuin family of deacetylases comprises seven members, of which the mitochondrial SIRTs play a role in metabolic homeostasis, and SIRT3 in particular regulates many mitochondrial processes and promotes cell survival by restricting reactive oxygen species (ROS) production and deacetylating cyclophilin D, a peptidyl-prolyl isomerase that activates the mitochondrial permeability transition pore[13,14,15,16,17]
Summary
Examined using a caecal ligation and puncture (CLP) model of sepsis-induced AKI in a SIRT3 knockout mouse model. Our results showed that CLP induced NLRP3 upregulation and this effect was significantly greater in SIRT3 KO than in WT mice (Fig. 3A). Consistent with these results, CLP-induced upregulation of ASC and caspase-1 was significantly higher in KO mice than in WT mice (Fig. 3B,C), confirming that SIRT3 protects kidney tissues from sepsis-induced inflammatory injury.
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