This study aimed to investigate the protective effects and underlying mechanisms of Panax notoginseng saponins (PNS) on glomerular endothelial cell (GEC) injury induced by high glucose, which is crucial in the development of diabetic nephropathy. GECs were treated with high glucose alone, PNS alone, or a combination of PNS and overexpression of endothelin-1 (ET-1), a key regulator in endothelial dysfunction. The results showed that high glucose inhibited cell viability, increased reactive oxygen species (ROS) levels, and upregulated the expression of fibronectin (FN), collagen type IV (Col-IV), protein kinase C (PKC), transforming growth factor-beta 1 (TGF-f31), and ET-1. Additionally, high glucose downregulated the expression of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). PNS treatment significantly protected against high glucose-induced GEC injury by promoting cell viability, reducing ROS generation,IP: downregulating203.8.109.20 FN,O : Col-IV,Tue, 10PKC, Oct TGF-f31, 2023 12:11and 53ET-1 expression, and upregulating SOD, GSH-Px, and CAT expression. Howeve, ET-1 ovrexpression reversed the potective effects of PNS, indicating the Copyright: American Scientific Publishers involvement of the ET-1/protein kinase C (PKC)/TGF-f31 pathway. In conclusion, PNS demonstrated a protective effect Delivered by Ingenta against high glucose-induced GEC injury by inhibiting the ET-1/PKC/TGF-f31 pathway. These findings suggest that PNS may be a potential therapeutic target for diabetic nephropathy by antagonizing ET-1.