Resveratrol alleviates glucolipid metabolism disorders in diabetic nephropathy via the HIF-1α pathway: a network pharmacology and experimental validation study

Background Diabetic nephropathy (DN) represents a major microvascular complication of diabetes with complex pathogenesis. Resveratrol (RSV), a polyphenol from Polygonum cuspidatum , is a potential therapeutic agent for DN. However, the exact mechanisms of RSV modulating glucolipid metabolism in DN remain unclear. Methods Potential targets and signaling pathways of RSV against DN were predicted by network pharmacology and molecular docking. Based on the prediction, a DN model was generated in male Wistar rats using a high-fat diet/streptozotocin (HFD/STZ) induction, followed by 12-week RSV (30 mg/kg/d) for in vivo validation. In vitro , HK-2 cells cultured in palmitic acid (PA) were treated with either RSV or LW6, a hypoxia-inducible factor 1α (HIF-1α) inhibitor. Biochemical parameters, histopathological alterations and lipid deposition were examined. AKT/HIF-1α pathway activation and downstream metabolic gene levels were analyzed via Western blot, immunofluorescence and RT-qPCR. Results Bioinformatics findings revealed RSV exerts its anti-DN effects predominantly through the prioritized candidate AKT1 and the highly enriched HIF-1 signaling pathway. In vivo , RSV significantly ameliorated hyperglycemia and renal dysfunction and alleviated histopathological injuries and glycogen storage. Mechanistically, RSV suppressed p-AKT and HIF-1α expression, reduced Glut1 mRNA levels, and elevated Ldlr mRNA levels, significantly. In vitro , RSV effectively decreased lipid accumulation and inhibited HIF-1α expression, downregulating SREBP1, SREBP2, LDLR, GLUT1 and TGF-β1 and upregulating INSIG2. The effects of LW6 were largely consistent with those of RSV but failed to reduce HIF-1α mRNA levels. Conclusion The attenuation of glucolipid metabolic disorders in DN by RSV is associated with suppression of the HIF-1α pathway, highlighting the therapeutic potential of RSV for DN.