Mitochondrial activity contributes to impaired renal metabolic homeostasis and renal pathology in STZ-induced diabetic mice.

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, but the efficacy of current therapeutic strategies on DN remains unsatisfactory. Recent research has reported the involvement of metabolic rearrangement in the pathological process of DN, and of all the disturbances in metabolism, mitochondria serve as key regulatory hubs. In the present study, high-resolution mass spectrometry-based nontarget metabolomics was used to uncover the metabolic characteristics of the early diabetic kidney with or without the inhibition of mitochondrial activity. At first, we observed a moderate enhancement of mitochondrial complex-1 activity in the diabetic kidney, which was completely normalized by the specific mitochondrial complex-1 inhibitor rotenone (ROT). Meanwhile, metabolomics data indicated an overactivated pentose phosphate pathway, purine and pyrimidine metabolism, hexosamine biosynthetic pathway, and tricarboxylic acid cycle, which were strikingly corrected by ROT. In addition, ROT also strikingly corrected imbalanced redox homeostasis, possibly by increasing the ratio of antioxidant metabolites glutathione and NADPH against their oxidative form. In agreement with the improved metabolic status and oxidative response, ROT attenuated glomerular and tubular injury efficiently. Fibrotic markers (fibronectin, α-smooth muscle actin, collagen type I, and collagen type III), inflammatory factors (TNF-α, IL-1β, and ICAM-1), and oxidative stress were all markedly blocked by ROT. In vitro, ROT dose dependently attenuated high glucose-induced proliferation and extracellular matrix production in mesangial cells. Collectively, these findings revealed that the overactivation of mitochondrial activity in the kidney could contribute to metabolic disorders and the pathogenesis of early DN.