Decursin ameliorates diabetic kidney disease by attenuating renal epithelial-mesenchymal transition via inhibition of the PI3K/Akt pathway

OBJECTIVE: This study aims to elucidate the therapeutic mechanisms of Decursin (DE) against diabetic kidney disease (DKD), focusing on its effects on renal epithelial-mesenchymal transition (EMT) and the underlying signaling pathways. METHODS: A streptozotocin (STZ)-induced DKD model was established in rats and treated with DE for 12 weeks. Metabolic and renal function indices were assessed using blood and urine samples, while kidney tissues were subjected to histopathological examination. Network pharmacology and disease database analyses were employed to predict the core target genes of DE in DKD. The predicted targets and EMT-related processes were further validated using human renal tubular epithelial cells (HK2) under high glucose (HG) or transforming growth factor-beta 1 (TGF-β1) stimulation. The expression of core target proteins and EMT markers was evaluated by Western blotting in both in vivo and in vitro settings. RESULTS: DE treatment significantly ameliorated biochemical parameters and renal EMT in DKD rats. Network analysis identified 16 potential target genes, with MMP-9, ESR1, PTGS2, AR, and CTNNB1 ranked as the top five core genes. Molecular docking and protein-protein interaction analysis further prioritized MMP-9, PI3K, and Akt as the most promising hub targets of DE. Consistently, Western blot analysis confirmed that DE markedly downregulated the expression of PI3K, phosphorylated Akt (p-Akt), and EMT-related proteins (including MMP-9, N-cadherin, and α-SMA) both in DKD rat kidneys and in HG- or TGF-β1-stimulated HK2 cells. Furthermore, the PI3K inhibitor LY294002 produced similar anti-EMT effects, thereby confirming the involvement of the PI3K/Akt pathway in the action of DE. CONCLUSION: Integrating experimental and network pharmacology approaches, this study demonstrates that DE alleviates renal EMT in DKD by inhibiting the PI3K/Akt signaling pathway, providing preliminary evidence for future studies.