Apigenin Combined with Aerobic Exercise Is Associated with Attenuated Renal Oxidative Stress and AMPK/SIRT1/PGC-1α Pathway Activation in NAFLD Mice

Non-alcoholic fatty liver disease (NAFLD) induces renal injury via the liver–kidney axis, with oxidative stress as the core pathological mechanism. Apigenin (API) and aerobic exercise (AE) exhibit antioxidant and metabolic regulatory properties, but their combined renoprotective effect in NAFLD and the underlying mechanism remain poorly characterized. This study aimed to explore the protective efficacy of API combined with AE against NAFLD-associated renal damage and its association with the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway. A NAFLD mouse model was established via 12-week high-fat-diet feeding, followed by 8-week API intraperitoneal injection and/or treadmill AE intervention. Renal histology, biochemical parameters, inflammatory cytokines, tubular injury markers, and pathway molecules were examined. Combined intervention significantly reduced serum creatinine (SCr) and blood urea nitrogen (BUN), alleviated renal lipid accumulation, and attenuated oxidative stress and inflammation. It significantly downregulated the tubular injury marker KIM-1, and induced a downward trend in NGAL and L-FABP without statistical significance. The combined intervention also enhanced AMPK phosphorylation and upregulated SIRT1 and PGC-1α protein expression, with greater effects than single interventions and significant statistical interactions between the two interventions on these pathway molecules. These results suggest that API combined with AE attenuates NAFLD-related renal injury, and that this protective effect is associated with the upregulation of AMPK phosphorylation and SIRT1/PGC-1α protein expression, the significant statistical interaction between the two interventions suggests the potential involvement of this pathway in mediating renoprotection. These findings provide preliminary evidence for the association between the AMPK/SIRT1/PGC-1α pathway and the renoprotective effect of this combined intervention strategy.