Therapeutic effect of RAGE-targeted azeliragon therapy in ER stress-mediated diabetic retinopathy

Diabetes Mellitus represents a significant health concern in contemporary society. Diabetic retinopathy is a significant microvascular complication of diabetes, representing one of the leading causes of blindness worldwide. Various factors, including chronic hyperglycemia, inflammation, oxidative stress from reactive oxygen radicals, and endoplasmic reticulum stress, contribute to cellular ischemia and trigger apoptosis, resulting in manifestations that range from mild retinopathy to severe vision-threatening conditions. Existing treatments for diabetic retinopathy are often inadequate, prompting ongoing research into more effective therapeutic options. Numerous metabolic pathways have been implicated in the pathogenesis of diabetic retinopathy, one of which involves advanced glycation end products. These products, which accumulate due to hyperglycemia, contribute to diabetic retinopathy by interacting with their receptors. In this study, a diabetic retinopathy model was established using a human retina pigment epithelium cell line exposed to advanced glycation end products +glucose+lipopolysaccharide based on previous research. Azeliragon, an advanced glycation end products receptor inhibitor was applied to diabetic cells in doses of 100 nM, 300 nM, and 500 nM for 72 hours. Subsequently, we analyzed the mRNA expressions of various target genes involved in diabetic retinopathy pathogenesis. The experimental groups included a control group, a diabetic retinopathy group and groups treated with Azeliragon. Statistical comparisons were carried out using ANOVA and Tukey tests to evaluate the effects of Azeliragon on diabetic retinopathy. Our analysis focused on key genes associated with angiogenesis, inflammation, endoplasmic reticulum stress, oxidative stress, and apoptosis. Notably, the high-dose Azeliragon treatment group exhibited suppressed inflammation, angiogenesis, and apoptosis in diabetic cells. Additionally, In we observed a decrease in the mRNA expression of genes associated with endoplasmic reticulum stress and the increase in the mRNA expression which was associated with improved protein folding capacity. Keywords: Diabetic retinopathy, endoplasmic reticulum (ER) stress, Azeliragon, advanced glycation end products (AGE), AGE receptor (RAGE), ARPE-19 In conclusion, our in vitro findings suggest that Azeliragon may serve as a potential therapeutic agent in the treatment of endoplasmic reticulum stress-mediated diabetic retinopathy.