Differential Effects of Retinol-Binding Protein 3 and Anti-VEGF Antibodies on Retinal Dysfunctions in Diabetic Retinopathy.

Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective treatment of severe diabetic retinopathy (DR) and macular edema, but a significant subset of people showed inadequate response to anti-VEGF intervention. Since elevation or overexpressing retinol binding protein 3 (RBP3) decreased risks for retinal pathologies and progression to severe DR, we compared the therapeutic profile of RBP3 and anti-VEGF to normalize retinal dysfunctions induced by diabetes. Intravitreous injection of recombinant human RBP3 (rhRBP3) and anti-VEGF antibodies (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 VEGFR2 expressions and tyrosine phosphorylation of VEGFR. Only rhRBP3 ameliorated diabetes induced reduction of neural retinal function, measured by electroretinogram. Further, rhRBP3 reduced retinal expressions of inflammatory cytokines (TNFα and IL6) in retinal pigmented epithelial and Müller cells exposed to hyperglycemia. Metabolic studies, using Seahorse, showed only rhRBP3 normalized retinal glycolytic rates in diabetic rats. Thus, both intravitreous anti-VEGF antibodies and RBP3 injections normalized retinal vascular dysfunctions caused by diabetes. Only RBP3 targeted both neural and vascular retina to reduce glycolytic rates, reversed neural-retinal dysfunctions, and reduced inflammatory cytokines induced by diabetes, to delay early changes of DR.