Phellodendron amurense Rupr. Polysaccharides protects against diabetic nephropathy via alteration of PI3K/GSK-3β/Nrf2/TGF-β/Smad signaling pathway and gut microbiota

In this study, a diabetic nephropathy (DN) rat model was established using 2% Streptozocin (STZ) solution, and an in vitro DN model was constructed by stimulating HK-2 cells with 30 mM glucose to investigate the mechanism of Phellodendron amurense Rupr. Polysaccharides (PAP) in ameliorating DN. Results demonstrated that PAP, a neutral homogeneous polysaccharide with molecular weight of 1.98 × 105 Da composed of Rha, GalA, Gal, and D-Xyl, exerted renal protective effects through multiple pathways. It enhanced renal antioxidant capacity and alleviated oxidative damage in DN by upregulating PI3K/AKT pathway-related protein expression. Simultaneously, PAP activated the TGF-β/Smad pathway via Nrf2 to mitigate renal fibrosis symptoms in DN, while inhibiting cellular apoptosis. Furthermore, PAP suppressed renal inflammation through gut microbiota reduction, thereby protecting against renal injury in DN rats. This study reveals that PAP alleviates DN symptoms by modulating gut microbiota, enhancing antioxidant and anti-fibrotic capacities, and inhibiting apoptotic pathways, comprehensively elucidating its multifaceted therapeutic mechanisms against DN.