Nrf2‐Mediated Ferroptosis Is Involved in Berberine‐Induced Alleviation of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the most common and serious complication of diabetes mellitus. Currently, there is a lack of safe and effective preventive strategies for DKD. The study aimed to explore the preventive effects and potential mechanisms of berberine (BBR) against DKD. In the in vivo experiments, we established a DKD rat model induced by the combination of high-fat diet and streptozotocin to investigate the preventive effect of BBR on DKD. Subsequently, in vitro experiments using human renal tubular epithelial cells (HK-2 cells) were performed to further validate the effect of BBR on renal tubular epithelial cell ferroptosis induced by advanced glycation end products (AGEs). In vivo, we found that BBR improved renal function and attenuated inflammatory cell infiltration, podocyte injury, and iron deposition in renal tissue in DKD rats. In addition, in vitro experiments showed that BBR attenuated HK-2 cell ferroptosis induced by AGEs. We further identified Nrf2 as a direct binding target of BBR by molecular docking and Surface Plasmon Resonance (SPR). Then, immunohistochemistry and Western Blot results demonstrated that BBR could activate the Nrf2 pathway, initiate the endogenous antioxidant system, and inhibit the occurrence of AGEs-induced ferroptosis. Moreover, silencing of Nrf2 by siRNA technology eliminated the protective effect of BBR on AGEs-induced ferroptosis. Collectively, our results supported that BBR could inhibit oxidative stress and ferroptosis by targeting activation of the Nrf2 pathway, thereby delaying the disease progression of DKD, providing a new scientific basis and perspective for the prevention and treatment of DKD.