Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury.
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.
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
Wen-Yu
WY
Zhao
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
Lei
L
Zhang
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
Ming-Xing
MX
Sui
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
You-Hua
YH
Zhu
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
Li
L
Zeng
D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D058847:Inflammasomes; D017382:Reactive Oxygen Species; D056566:Sirtuin 3