Astragalus polysaccharide alleviates diabetic nephropathy via SIRT1-dependent activation of FOXO3a/BNIP3 pathway to enhance podocyte autophagy

Astragalus polysaccharide (APS), a major bioactive component of Astragalus membranaceus, has received considerable attention for its potential in treating diabetes and its complications. However, whether its renoprotective effects in diabetic nephropathy (DN) involve autophagy modulation remains poorly understood. Here, Streptozotocin (STZ)-induced DN rats and high glucose (HG)-exposed mouse podocyte clone-5 (MPC5) cells were established as in vivo and in vitro models, respectively. APS effects were evaluated using renal function indicators, renal histopathology, and autophagy markers. Autophagic flux was assessed by MDC staining and transmission electron microscopy (TEM). Furthermore, SIRT1 silencing or overexpression in vitro was used to confirm its role in regulating autophagy and its interaction with the FOXO3a/BNIP3 pathway. APS treatment significantly reduced fasting blood glucose proteinuria, and glomerular hypertrophy in DN rats. Mechanistically, APS upregulated SIRT1 deacetylase activity, promoted FOXO3a nuclear translocation and activated BNIP3-mediated podocyte autophagy. In vitro, APS restored autophagic flux in MPC5 cells, evidenced by increased Beclin 1 expression, elevated LC3 II/LC3 I ratio and reduced p62 accumulation. MDC staining and TEM further confirmed enhanced autophagosome formation in podocytes following APS treatment. These findings demonstrate APS alleviates DN by enhancing podocyte autophagy via the SIRT1/FOXO3a/BNIP3 axis, thereby protecting renal function.