Local RAGE Inhibition Attenuates Early Diabetic Retinal Pathology in Streptozotocin-Induced Rats

Introduction Diabetic retinopathy, which occurs during extended periods of chronic hyperglycemia, is one of the main causes of vision loss. The receptor for advanced glycation end products (RAGE) plays a central role in inflammatory and angiogenic signaling, both of which contribute to the pathogenesis of diabetic retinopathy, but its therapeutic targeting in ocular disease has been insufficiently explored. Methods We evaluated topical RAGE229, a small-molecule RAGE inhibitor, and an intravitreally administered anti-RAGE antibody in a streptozotocin-induced diabetic rat model. At day 84, treatment effects were assessed using masked fundoscopic scoring, RT-qPCR, immunohistochemistry, and histological morphometry. Treated eyes were evaluated against both route-matched diabetic vehicle-control groups and paired contralateral vehicle-treated eyes. Results Both interventions reduced fundoscopic pathology and retinal Vegfa and Nfkb1 expression, whereas Ager showed only a non-significant downward trend. NF-κB p65 immunoreactivity was reduced by both treatments, while a significant reduction in VEGF-A immunoreactivity was detected only in the paired anti-RAGE antibody analysis. Morphometric analysis indicated attenuation of diabetes-associated retinal thinning with both interventions. Neither intervention altered systemic glycemic control. Although both interventions demonstrated similar overall anatomical protection, anti-RAGE antibody treatment showed more consistent effects across protein-level and structural endpoints. Conclusion These findings provide proof-of-concept evidence that local RAGE-targeted treatment may attenuate vascular, molecular, and structural manifestations of early experimental diabetic retinopathy without detectable changes in systemic glycemia. Further preclinical studies should evaluate ocular exposure, direct target engagement, functional visual outcomes, and reproducibility in larger cohorts.