Differential Effects of Retinol-Binding Protein 3 and Anti-VEGF Antibodies on Retinal Dysfunctions in Diabetic
Qin Li1,2, Satoru Onizuka2, Kyoungmin Park2,3,4
1Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
