Resveratrol attenuates tubular injury in diabetic kidney disease by suppressing the ferroptosis–ferritinophagy pathway

Abstract

Abstract Background Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and renal oxidative stress (OS)–mediated tubular injury plays a critical role in its progression. Resveratrol (Res) possesses established antioxidative properties, yet its mechanistic involvement in ferroptosis-ferritinophagy signaling remains unclear. This study investigated the protective effects of Res on renal tubular injury in DKD and explored its regulatory role in the ferroptosis–ferritinophagy pathway. Methods A DKD mouse model was established using unilateral nephrectomy followed by streptozotocin injection. A total of 42 male C57BL/6 N mice were used in this study. Six mice served as the blank control group, and the remaining 36 underwent model induction. The 30 successfully modeled mice were randomly divided into 5 groups ( n = 6 per group): the DKD group, the positive control group (perindopril 0.48 mg/kg/d), and the resveratrol (Res) low-, medium-, and high-dose groups (1.0, 2.5, 5.0 mg/kg/d, administered by gavage for 8 weeks). Renal function, oxidative stress markers, and renal tubular injury markers were assessed. Hematoxylin and eosin (H&E) staining, Masson staining, 4-hydroxynonenal (4-HNE) immunofluorescence, and Western blotting (for ferroptosis/ferritinophagy-related proteins) were performed. Results Compared with the Black group, DKD group mice exhibited marked OS, tubular injury, and activation of the ferroptosis–ferritinophagy axis. Res treatment significantly reduced fasting blood glucose, SCr, BUN, 24-hour urinary protein, MDA, Fe²⁺, β2-MG, RBP4, and NGAL levels, while elevating T-SOD and GSH-Px ( P < 0.05). Res also downregulated Nrf2, SLC7A11, GPX4, LC3II/LC3I, and FTH1, alongside increased expression of p62 and NCOA4, demonstrating a clear dose-dependent effect. Conclusion Resveratrol markedly attenuates renal oxidative stress and tubular injury in DKD. These findings suggest that its renoprotective effects may be mediated through inhibition of the ferroptosis–ferritinophagy pathway, highlighting Res as a promising therapeutic candidate for DKD.