Astragaloside IV Ameliorates Diabetic Kidney Disease via Inhibiting MAPK Pathway and Alleviating Metabolic Dysregulation

Diabetic kidney disease (DKD) is a severe diabetic microvascular complication with a complex pathogenesis and progression driven by renal fibrosis and inflammation. As a condition, DKD imposes a heavy clinical burden. Astragaloside IV (AS-IV), the main active component of Astragalus membranaceus, exhibits renoprotective potential in DKD, but its molecular mechanisms remain unclear. This study combined network pharmacology, molecular docking, and in vivo validation in db/db mice in order to explore AS-IV's therapeutic effect on DKD and the mechanisms by which it alleviates inflammation and fibrosis. The efficacy of AS-IV was evaluated via glucose metabolism, urinary protein, hepatic/renal function, and renal histopathology using H&E, PAS, Masson staining, and transmission electron microscopy. The expressions of the MAPK pathway, fibrosis and inflammation-related molecules were detected by ELISA, Western blot, RT-qPCR, immunohistochemistry and immunofluorescence. In addition, non-targeted metabolomics was used to explore metabolic regulation. Network pharmacology identified the MAPK pathway as a core target, and molecular docking confirmed AS-IV's strong binding to MAPK1/MAPK3. In vivo, AS-IV improved glucose metabolism, reduced albuminuria, alleviated renal histological damage, inhibited ERK/JNK/p38 phosphorylation in the MAPK pathway, downregulated fibrosis-related proteins (TGF-β1, α-SMA, Collagen I/IV) and suppressed NF-κB-mediated inflammation. It furthermore ameliorated metabolic disorders, and exhibited a particular efficacy in doing so for amino acid metabolism. Collectively, AS-IV retards DKD progression by both exerting antifibrotic/anti-inflammatory effects and correcting metabolic dysregulation via inhibition of the MAPK pathway. These mechanisms provide a theoretical basis for the clinical application of AS-IV in DKD.