Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury

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.

Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy

“…7A, F). This is consistent with a previous study showing that NAC inhibited the expression of NLRP3 protein (53).…”

“…ROS are well known activators of NLRP3 inflammasome. It is reported that NAC can block the transcription of NLRP3 and pro-IL-1b by scavenging of cellular ROS (53). Other research also found that mtROS scavengers can significantly inhibit the activation of NLRP3 inflammasome (53).…”

“…It is reported that NAC can block the transcription of NLRP3 and pro-IL-1b by scavenging of cellular ROS (53). Other research also found that mtROS scavengers can significantly inhibit the activation of NLRP3 inflammasome (53). A recent study reported that mtROS overproduction is associated with increases in NLRP3/IL-1b expression in the kidneys of patients with DN and in Lepr db /Lepr db mice (54).…”

NADPH oxidase inhibitor, diphenyleneiodonium prevents necroptosis in HK-2 cells

“…Various studies have demonstrated that excessive ROS promotes necroptosis in various cell types, whereas inhibiting ROS production reduces necroptosis (13)(14)(15)(16). In addition, previous studies revealed that ROS production is augmented in AKI, and that ROS lead to renal tubular epithelium injury via inflammasome activation, mitochondrion damage and tubular epithelium apoptosis (22)(23)(24)(25). To the best of our knowledge, there are no studies that have investigated the effect of ROS on necroptosis in renal tubular epithelium.…”

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

“…Indeed, overexpression of SIRT3 in THP-1 cells inhibited the activation of the NLRP3 inflammasome, whereas its knockdown stimulated its activation [91]. Not surprisingly, SIRT3 inhibits the NLRP3 inflammasome in a mouse model of sepsis-induced acute kidney injury by attenuating ROS production [92], and is also protective in a model of LPS-induced lethality [93]. SIRT3 deficiency accelerates the development of metabolic syndrome in mouse, and single nucleotide polymorphisms in the human SIRT3 gene have been associated with this condition [40].…”