Echinacoside attenuates unilateral ureteral obstruction-induced renal fibrosis through NGF/PI3K/PKCδ/Src signaling
Yingdan Zhao, Qingqing Wang, Zhihuan Tang, Xia Wu, Zifan He, Yayun He, Jing Yang, Jing Ge, Na Liu, Yunhai TangObjective
Renal fibrosis is a common irreversible pathological process leading to chronic kidney disease. Echinacoside (Ech) exhibits renoprotective properties, whereas its detailed regulatory mechanism against renal fibrosis remains poorly defined. This study aimed to investigate the therapeutic effect of Ech on renal fibrosis and further elucidate its underlying molecular mechanism.
Methods
A unilateral ureteral obstruction (UUO) mouse model was established, and mice received intraperitoneal injection of Ech at 20 or 40 mg/kg/day after surgery. H&E, Masson, Sirius Red and TUNEL staining were used to evaluate renal injury and tubular apoptosis. Inflammatory factors, EMT and extracellular matrix markers were detected by RTqPCR and immunofluorescence. Western blot analysis was performed to analyze the NGF/PI3K/PKCδ pathway. Molecular docking predicted the binding between Ech and Src kinase. An NGF neutralizing antibody was applied for functional verification.
Results
Ech treatment significantly ameliorated UUOtriggered renal histological damage, tubular apoptosis, inflammatory infiltration, and extracellular matrix accumulation. Mechanistically, Ech remarkably suppressed the overexpression of Ngf and inhibited the phosphorylation of PI3K, AKT, and Src, as well as downregulated Prkcd expression in UUO kidneys. Molecular docking results revealed a high binding affinity between Ech and Src kinase. Moreover, blockade of endogenous NGF effectively alleviated UUOinduced renal inflammation and fibrotic lesions, confirming the essential regulatory role of NGF in renal fibrosis progression.
Conclusions
Ech ameliorates renal inflammation and fibrosis by regulating the NGF/PI3K/PKCδ/Src signaling pathway, indicating that Ech may serve as a promising natural therapeutic agent for renal fibrosis.