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

Abstract

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.