Ginsenoside Rd ameliorates high glucose-induced retinal endothelial injury through AMPK-STRT1 interdependence

Diabetic retinopathy (DR) manifests as a complicated and blinding complication in diabetes mellitus. First-line treatments for advanced DR have shown ocular side-effects in some patients. Ginsenoside Rd (Rd), an active ingredient isolated from Panax notoginseng and P. ginseng, has demonstrated diverse and powerful activities on neuroprotection, anticancer and anti-inflammation, but its vascular protective effects have rarely been reported. Herein, this study aims to investigate the protective effects of Rd on retinal endothelial injury with emphasis on AMPK/SIRT1 interaction. The results indicated that Rd promoted AMPK activation and SIRT1 expression. Besides, Rd strengthened the interaction between AMPK and SIRT1 by increasing NAD⁺/NADH levels and LKB1 deacetylation in endothelial cells. Moreover, Rd reversed high glucose-induced activation of NOX2, oxidative stress, mitochondrial dysfunction, and endothelial apoptosis in an AMPK/SIRT1-interdependent manner. Hyperglycemia induced loss of endothelial cells and other retinal damage, which was restored by Rd via activating AMPK and SIRT1 in vivo. The enhancement of AMPK/SIRT1 interaction by Rd beneficially modulated oxidative stress and apoptosis, and ameliorated diabetes-driven vascular damage. These data also supported the evidence for Rd clinical development of pharmacological interventions and provided a novel potential vascular protective drug for early DR.