Background Phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN) is a primary cause of nephrotic syndrome in adults. Modified Guizhi plus Huangqi decoction (MGPHD) has been clinically effective for PLA2R MN. This basic study was designed to investigate the efficacy and mechanisms of MGPHD in treating PLA2R MN. Methods A PLA2R MN mouse model was established by intraperitoneal injection of anti‐PLA2R antibodies in transgenic mice expressing PLA2R1 in podocytes. Mice were administered MGPHD for 10 consecutive days. 24‐h urine volume, urinary albumin/creatinine, biochemical parameters, and renal pathological changes were assessed. Western blotting evaluated proteins related to PLA2R, podocyte cytoskeleton, autophagy, and AMPK/mTOR pathway in renal tissues. Astragaloside IV and icariin in MGPHD were detected by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). In vitro, anti‐PLA2R antibodies were used to establish a podocyte injury model in podocytes (AB 8/13). Molecular docking assessed the binding of the two compounds to podocyte cytoskeleton proteins. Western blot detection of related proteins in vitro was consistent with the results obtained in vivo. Results MGPHD treatment improved podocyte injury, increased 24‐h urine volume and serum albumin, and decreased urinary albumin/creatinine and serum cholesterol ( p < 0.05). Immunofluorescence showed a reduced deposition of PLA2R antigen and complement C3, and electron microscopy demonstrated a restored foot process morphology. Western blotting revealed downregulated PLA2R, P62, and p ‐mTOR/mTOR and upregulated α ‐actinin‐4, LC3II/I, and p ‐AMPK/AMPK ( p < 0.05). Anti‐PLA2R antibodies caused podocyte cytoskeleton rearrangement and autophagy‐related marker impairment in vitro, roughly consistent with in vivo Western blotting results. Molecular docking showed a stable binding of astragaloside IV and icariin to podocyte cytoskeleton proteins. Astragaloside IV and icariin at different doses protected podocytes by stabilizing AMPK/mTOR pathway autophagy‐related markers and reducing anti‐PLA2R antibody–induced injury. Conclusions MGPHD and its active components, astragaloside IV and icariin, effectively ameliorate anti‐PLA2R antibody–induced podocyte injury by partially restoring the podocyte cytoskeleton and modulating autophagy‐related markers, possibly through the AMPK/mTOR pathway.
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