Asiaticoside and asiatic acid improve diabetic nephropathy by restoring podocyte autophagy and improving gut microbiota dysbiosis.

Diabetic nephropathy (DN) is a common and severe complication of diabetes. Despite the availability of several drugs for the treatment of DN, there remains a need for novel therapeutic agents with more favorable risk profiles. Asiaticoside (AT) and asiatic acid (AA), two bioactive constituents derived from Centella asiatica, have exerted excellent anti-inflammatory properties. However, the effect and underlying mechanism of AT and AA on DN remains unclear. To investigate the effect and underlying mechanism of AT and AA on DN in mice, a high-fat diet- and streptozotocin-induced diabetic mice model was constructed to induce DN symptoms. AT and AA were then administered for 6 weeks to determine their impact on the progression of DN. The results indicated that AT and AA treatment improved insulin resistance and lipid metabolism while reducing inflammation in the liver and adipose tissue of DN mice. Additionally, AT and AA protected kidney function and alleviated kidney inflammation and fibrosis. Mechanistically, AT and AA mitigated podocyte damage by activating autophagy, and these effects were abrogated after autophagy was inhibited by 3-methyladenine in vitro. AT and AA treatment protected gut barrier function, altered microbial composition and metabolites, and resulted in a reciprocal increase in beneficial bacteria and metabolites and a decrease in harmful ones. In summary, AT and AA administration ameliorated the progression of DN by activating podocyte autophagy and regulating microbiota dysbiosis, laying a theoretical basis for the nutritional intervention of AT and AA in DN.