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Sirt3 overexpression alleviates hyperglycemia-induced vascular inflammation through regulating redox balance, cell survival, and AMPK-mediated mitochondrial homeostasis

Abstract Context: Sirtuin-3 (Sirt3), a NAD-dependent deacetylase, has been reported to be involved in many biological processes. Objective: The present study aimed to investigate the effect and mechanism of Sirt3 on diabetic mice and human umbilical vein endothelial cells (HUVECs) under high glucose (HG) condition. Materials and methods: HUVECs were cultured under HG and inflammation pathway was determined via qPCR, western blots, and immunofluorescence. Results: Sirt3 expression was reduced in the progression of diabetic nephropathy. Overexpression of Sirt3 sustains renal function and retard the development of diabetic nephropathy. Mechanistically, Sirt3 overexpression attenuated hyperglycemia-mediated endothelial cells apoptosis in kidney. Besides, Sirt3 overexpression repressed oxidative injury and blocked caspase-9-related apoptosis pathway. Moreover, we found that Sirt3 overexpression was associated with AMPK activation and the latter elevates PGC1α-related mitochondrial protective system, especially mitochondrial autophagy. Loss of opa1 and/or inhibition of AMPK could depress mitochondrial autophagy and exacerbates mitochondrial function, finally contributing to the death of human renal mesangial cells. Conclusions: Our results demonstrated the beneficial effects of Sirt3 in the progression of diabetic nephropathy. Increased Sirt3-activated AMPK pathway, augments PGC1α-related mitochondrial protective system, sustained redox balance and closed caspase-9-involved apoptosis pathway in the setting of diabetic nephropathy.