Protective effect of Cyanidin-3-O-glucoside from blueberry anthocyanin extracts against hyperglycemia-induced outer BRB damage by suppressing REDD1-mediated VEGFA upregulation

Abstract

Diabetic retinopathy (DR), caused by hyperglycemia, has been becoming the tremendous public health threaten globally. Recently, there has been a growing interest in using natural bioactive products for dietary intervention to manage the progression of DR. In this study, we utilized the streptozotocin (STZ)-induced retinopathy model in C57BL/6 J mice to investigate the impact of blueberry anthocyanin extract (BAEs) on the retinal cells of diabetic mice and assess the antioxidant activity of BAEs. Our results indicate that BAEs intervention significantly improved oxidative stress and inflammation levels in the retina of STZ-induced diabetic mice by downregulating the expression of regulated in development and DNA damage 1 (REDD1) in the choroid-retinal pigment epithelium (choroid-RPE). Cyanidin-3-O-glucoside (C3G), a primary component of BAEs, was further examined to explore potential molecular mechanisms. Our findings suggest that upregulation of REDD1 led to increase the vascular endothelial growth factor A (VEGFA) expression in ARPE-19 cells exposed to high glucose (HG); however, intervention with C3G mediated REDD1-driven VEGFA transcription and mitigated HG-induced changes in cell injury by regulating intracellular redox balance. The knockout of REDD1 effectively reversed HG-induced alterations in VEGFA levels, confirming the crucial role of REDD1 in the regulating of retinal vascular permeability factors. Overall, BAEs demonstrate potential in alleviating HG-induced DR, with the key component C3G exerting significant effects by inhibiting REDD1 activity and its downstream signaling pathways. These findings underscore the potential of REDD1 as a target for mitigating hyperglycemia-induced retinopathy and emphasize the value of BAEs as a dietary intervention strategy.