Sirtuin 3 deficiency promotes acute kidney injury induced by sepsis via mitochondrial dysfunction and apoptosis

Document Type : Original Article


Department of Intensive Care Unit, Ningbo First Hospital, Ningbo, Zhejiang Province, P.R China


Objective(s): To explore the regulation mechanism of Sirtuin 3 (SIRT3) on the mitochondrial function and apoptosis of acute kidney injury (AKI) in septic mice.
Materials and Methods: The sepsis-induced AKI model was constructed in the wild-type and SIRT3 knockout (KO) mice, and the levels of serum creatinine (Scr) and plasma kidney injury molecule 1 (pKIM-1) in mice were detected by ELISA. The mitochondrial damage of kidney tubular epithelial cells (KTEC) was observed by electron microscopy, the apoptosis of KTEC was detected by TUNEL assay, and the mRNA levels of SIRT3, Bax, Caspase-3, and Bcl-2 were detected by RT-qPCR.
Results: SIRT3 KO caused increased expression of Scr, pKIM-1, and inducible nitric oxide synthase protein in the kidneys of septic mice, and decreased the levels of superoxide dismutase, catalase, and mitochondrial complex enzymes I/II/III/IV. SIRT3 deficiency exacerbated histopathological and mitochondrial damage to the proximal tubules of the kidney. In addition, SIRT3 KO resulted in a significantly increased apoptosis of KTEC, increased the mRNA levels of Bax and Caspase-3, and decreased the mRNA levels of Bcl-2.
Conclusion: Our study suggests that SIRT3 deficiency promotes sepsis-induced AKI via increasing oxidative stress, mitochondrial dysfunction, and inducing apoptosis.


1.    Bellomo R, Kellum JA, Ronco C, Wald R, Martensson J, Maiden M, et al. Acute kidney injury in sepsis. Intensive Care Med 2017; 43:816-828.
2.    Poston JT, Koyner JL. Sepsis associated acute kidney injury. BMJ 2019; 364: k4891.
3.    Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019; 96:1083-1099.
4.    Fan H, Zhao Y, Chen GD, Sun Min, Zhu JH. Health insurance status and risk factors of mortality in patients with septic acute kidney injury in Ningbo, China. J Int Med Res 2019; 47:370-376.
5.    McDonnell E, Peterson BS, Bomze HM, Hirschey MD. SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab 2015; 26:486-492.
6.    Morigi M, Perico L, Rota C, Longaretti L, Conti S, Rottoli D, et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest 2015; 125:715-726.
7.    Li Y, Ye Z, Lai W, Rao J, Huang W, Zhang X, et al. Activation of sirtuin 3 by silybin attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Front Pharmacol 2017; 8:178.
8.    Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress. Mol Cell 2011; 42: 561-568.
9.    Guo X, Yan F, Shan X, Li J, Yang Y, Zhang J, et al. SIRT3 inhibits Ang II-induced transdiferentiation of cardiac fbroblasts through β-catenin/PPAR-γ signaling. Life Sci 2017; 186:111-117.
10.    Fan H, Zhao Y, Zhu JH. S-nitrosoglutathione protects lipopolysaccharide-induced acute kidney injury by inhibiting toll-like receptor 4-nuclear factor-κB signal pathway. J Pharm Pharmacol 2019; 71:1255-1261.
11.    Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury. Sci Rep 2016; 6:33201.
12.    Brooks C, Wei Q, Cho SG, Dong Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest 2009; 119:1275-1285.
13.    Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E. Protective efect of curcumin against contrast induced nephropathy in rat kidney: what is happening to oxidative stress, infammation, autophagy and apoptosis. Eur Rev Med Pharmacol Sci 2014; 18: 461-470.
14.    Fan H, Le JW, Zhu JH. Protective effect of N-acetylcysteine pretreatment on acute kidney injury in septic rats. J Surg Res 2020; 254: 125-134.
15.    Je┼żek J, Cooper KF, Strich R. Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression. Antioxidants (Basel) 2018;7:13.
16.    Wu Y, Wang L, Wang X, Wang Y, Zhang Q, Liu W. Renalase contributes to protection against renal fibrosis via inhibiting oxidative stress in rats. Int Urol Nephrol 2018; 50:1347-1354.
17.    Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, et al. Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. J Cell Biol 2014; 206:289-305.
18.    Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, Bidani AK. Acute kidney injury: A springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 2010; 298:F1078-1094.
19.    Linkermann A, Chen G, Dong G, Kunzendorf U, Krautwald S, Dong Z. Regulated cell death in AKI. J Am Soc Nephrol 2014; 25:2689-2701.
20.    Galluzzi L, Kepp O, Kroemer G. Mitochondria: Master regulators of danger signalling. Nat Rev Mol Cell Biol 2012; 13:780-788.
21.    Huang YT, Chen YY, Lai YH, Cheng CC, Lin TC, Su YS, et al. Resveratrol alleviates the cytotoxicity induced by the radiocontrast agent, ioxitalamate, by reducing the production of reactive oxygen species in HK-2 human renal proximal tubule epithelial cells in vitro. Int J Mol Med 2016; 37:83-91.