Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaau6627
DOI: 10.1126/scitranslmed.aau6627

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Endogenous protection

Diabetic retinopathy (DR) is one of the most common consequences of diabetes affecting more than 35% of patients. Endogenous protective factors could explain why only a fraction of patients with diabetes develop DR. In this study, Yokomizo et al. analyzed data from a large cohort of patients with diabetes (Mendalist cohort) and showed that retinol binding protein 3 (RBP3) expression was negatively correlated with DR severity. Intravitreal RBP3 injection or retinal RBP3 overexpression in rodents protected against vascular endothelial growth factor– and diabetes-induced vascular retinal permeability. The protective effects were mediated by inhibition of glucose uptake in retinal endothelial and Müller cells.


The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

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