Anti–vascular endothelial growth factor (anti-VEGF) therapies are effective treatment for severe diabetic retinopathy (DR) and macular edema, but a significant subset of people had inadequate response to anti-VEGF intervention. Because elevation or overexpression of retinol binding protein 3 (RBP3) decreases risks for retinal pathologies and progression to severe DR, we compared the therapeutic profiles of RBP3 and anti-VEGF antibody to normalize retinal dysfunctions induced by diabetes. Intravitreous injection of recombinant human RBP3 (rhRBP3) and anti-VEGF antibody (namely, bevacizumab) inhibited retinal vascular permeability in Lewis rats induced by VEGF-A or after 2 months of diabetes induced by streptozotocin, in parallel with reductions of retinal VEGF and VEGF receptor 2 expressions and tyrosine phosphorylation of VEGF receptor. Only rhRBP3 ameliorated diabetes-induced reduction of neural retinal function, measured by electroretinogram. Furthermore, rhRBP3 reduced retinal expressions of inflammatory cytokines (TNF-α and IL-6) in retinal pigmented epithelial and Müller cells exposed to hyperglycemia. Metabolic studies, using a Seahorse flux analyzer, showed only rhRBP3 normalized retinal glycolytic rates in diabetic rats. Thus, both intravitreous anti-VEGF antibody and RBP3 injections normalized retinal vascular dysfunctions caused by diabetes. Only RBP3 targeted both neural and vascular retina to reduce glycolytic rates, reverse neural-retinal dysfunctions, and reduce inflammatory cytokines induced by diabetes, to delay early changes of DR.

Article Highlights

  • The therapeutic profile of an anti–vascular endothelial growth factor (anti-VEGF) antibody (bevacizumab), the established treatment for severe diabetic retinopathy (DR), was compared with that of a neural-retinal protein (retinal binding protein 3 [RBP3]) for ability to reverse retinal neuronal and vascular changes in diabetic rodents.

  • Both bevacizumab and RBP3 neutralized the actions of VEGF and vascular abnormalities, but only RBP3 reversed neural-retinal dysfunctions induced by diabetes.

  • Only RBP3 also normalized the glycolytic rates in the retina of diabetic rats.

  • Thus, RBP3 could therapeutically target both neural and vascular abnormalities related to early stages of DR.

This article contains supplementary material online at https://doi.org/10.2337/figshare.28359869.

© 2025 by the American Diabetes Association
2025
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