Dapagliflozin attenuates cellular senescence and mitochondrial dysfunction in diabetic kidney disease: potential involvement of AMPK/Sirt3 signaling.
Cellular senescence contributes to the pathology of diabetic kidney disease (DKD). Besides, mitochondrial dysfunction and cellular senescence are closely associated pathological processes that may influence one another during kidney injury progression. Dapagliflozin has demonstrated its renal protective benefits independent of the glucose-lowering effects, yet whether it acts via modulating cellular senescence is poorly understood. The design of our study is to explore the potential renal protective mechanism of dapagliflozin, focusing on cellular senescence and mitochondrial function. The streptozotocin-induced diabetic mice and high glucose-treated human renal tubular epithelial (HK-2) cells were used to achieve the purpose. We also employed Compound C and Sirt3 knockdown by small interfering RNA transfection to examine dapagliflozin's effect on AMPK/Sirt3 signalling pathway in HK-2 cell experiments. Dapagliflozin reduced the expression of renal senescence markers in both in vivo and in vitro experiments. Concurrently, dapagliflozin improved mitochondrial function, with evidence in mitochondrial membrane potential restoration, mitochondrial dynamics, and mitochondrial reactive oxygen species reduction, and lowered the levels of senescence-associated secretory phenotypes. Mechanistically, AMPK phosphorylation and Sirt3 expression level were attenuated by AMPK inhibitor compound C, which consequently attenuated dapagliflozin-mediated protective effects. Knockdown of Sirt3 in HK-2 cells substantially reduced dapagliflozin's improvements on mitochondrial function and its protective effects against cellular senescence, thereby reversing its alleviation of kidney function. Dapagliflozin treatment attenuated renal cellular senescence and improved mitochondrial function in DKD. Our findings support the involvement of AMPK/Sirt3 signaling in these renoprotective effects, as evidenced by the attenuation of dapagliflozin-mediated protection following AMPK inhibition and knockdown of Sirt3.