Gentianae Macrophyllae Radix inhibits renal fibrosis in type 2 diabetes via regulating aldose reductase

Ethnopharmacological relevance Gentianae Macrophyllae Radix (GMR), traditionally referred to as Qinjiao, consists of the desiccated roots derived from G. macrophylla Pall. Historically, this herb has been employed to alleviate edema, promote diuresis, quench thirst, and mitigate deficiency-related fever. Such clinical manifestations are commonly observed in patients suffering from diabetic kidney disease (DKD), a condition where renal fibrosis represents a critical pathological feature. Emerging evidence suggests that inhibiting aldose reductase (AR) could offer therapeutic benefits for DKD by ameliorating renal fibrosis. However, the scientific validation of GMR's efficacy in managing DKD remains lacking, and its potential influence on AR activity has not yet been investigated. Consequently, examining the capacity of GMR to modulate AR presents a promising avenue for DKD therapy.Aim of the study The present research conducted a thorough assessment of the anti-DKD properties of GMR with a specific focus on AR, intending to verify its therapeutic potency and elucidate the molecular mechanisms involved.Materials and methods To investigate the therapeutic potential of GMR against DKD and AR, we developed both in vivo and in vitro experimental systems. The in vivo model utilized C57BL/6 mice subjected to a high-fat diet combined with streptozotocin administration, whereas the in vitro approach involved culturing glomerular mesangial cells under high-glucose conditions. Additionally, we identified the primary constituents of GMR capable of entering the bloodstream and evaluated their specific roles in modulating DKD and AR progression.Results This findings indicate that GMR treatment effectively attenuates renal fibrosis associated with DKD and suppresses AR activity by stimulating the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway, which subsequently lowers oxidative stress levels. Notably, when AR was over-expressed in cell cultures, it reversed the Nrf2 pathway activation induced by GMR, thereby diminishing the compound's ability to alleviate oxidative damage and reduce fibrotic changes. Further analysis revealed that swertiamarin is the principal bioactive component of GMR found in the circulation. This molecule directly binds to AR, leading to the regulation of oxidative stress responses and the amelioration of renal fibrosis.Conclusion This research provides the initial evidence that GMR exerts a therapeutic effect on DKD by modulating AR activity, thereby mitigating oxidative stress. Swertiamarin, identified as the primary bioactive constituent in the bloodstream, functions as an inhibitor of AR.