Aerobic Exercise Ameliorates Renal Injury in High‐Fat Diet‐Fed Mice: A Novel Effect Mediated by the Drp1‐mtROS Pathway

AIM: Aberrant activation of dynamin-related protein 1 (Drp1) promotes excessive mitochondrial reactive oxygen species (mtROS) production; however, whether the Drp1-mtROS pathway mediates the renoprotective effects of aerobic exercise remains unclear. METHODS: High-fat diet (HFD)-fed mice were subjected to aerobic exercise or were intraperitoneally injected with the Drp1 inhibitor Mdivi-1 for 8 weeks. Fat mass, serum biochemical parameters, renal histopathology, mtROS production, oxidative stress-related markers, mitochondrial ultrastructure, mitochondrial membrane potential, ATP content, and protein expression were assessed. In parallel, Drp1 was knocked down in palmitic acid (PA)-treated HK-2 cells to further evaluate the role of the Drp1-mtROS pathway in lipid overload-induced renal tubular cell injury. RESULTS: Aerobic exercise reduced body weight and fat mass, improved circulating lipid profiles, and decreased serum creatinine and blood urea nitrogen levels in HFD-fed mice. Exercise also alleviated renal tubular injury, mesangial expansion, interstitial fibrosis, podocyte foot process effacement, and renal lipid accumulation. Mechanistically, aerobic exercise suppressed Drp1 phosphorylation at Ser616, reduced renal mtROS production and oxidative stress, improved mitochondrial morphology, restored mitochondrial membrane potential and ATP production, and modulated the expression of lipid-metabolism-related proteins. Pharmacological inhibition of Drp1 with Mdivi-1 largely reproduced the metabolic, mitochondrial, and renoprotective effects of aerobic exercise. Furthermore, Drp1 knockdown attenuated PA-induced mtROS accumulation, oxidative stress, mitochondrial dysfunction, and lipid deposition in HK-2 cells. CONCLUSION: Aerobic exercise exerts a protective effect on the kidneys of HFD-fed mice, at least in part, by inhibiting the Drp1-mtROS pathway. This provides insights into the benefits of aerobic exercise in obesity-related nephropathy.