Madecassoside and madecassic acid mitigates diabetic nephropathy via podocyte autophagy and gut microbiota in mice

Diabetic nephropathy (DN) is a common microvascular complication of diabetes with limited treatment options available. Madecassoside (MA) and madecassic acid (MCA) exhibit various pharmacological activities, while their effects on DN remain elusive. Here, we found that MA and MCA treatment mitigated insulin resistance, alleviated metabolic disorders, and attenuated systemic inflammation in high-fat diet- and streptozotocin-induced DN mice. In addition, MA and MCA administration alleviated the biochemical indicators for kidney function and reduced renal inflammation and fibrosis, thereby mitigating the progression of DN. These renal protective effects were partly mediated by the activation of podocyte autophagy. Moreover, MA and MCA protected the integrity of the gut barrier and altered the microbial composition and their metabolites, resulting in an enrichment of beneficial bacteria and metabolites and a reduction of the pathogenic bacteria and harmful metabolites. Therefore, MA and MCA alleviated DN by activating podocyte autophagy and regulating microbiota dysbiosis.