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Z. Ablonczy; Intraocular AGE Products Disrupt the Barrier Function of the RPE. Invest. Ophthalmol. Vis. Sci. 2008;49(13):171.
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The formation of advanced glycation end-products (AGEs) is accelerated in diabetes, playing a central role in diabetic complications. Although the extracellular environment in the outer retina is maintained by the retinal pigment epithelium (RPE), its role in diabetic retinopathy and macular edema has received little attention. This project investigates how AGEs modulate the barrier function of the RPE.
Trans-epithelial resistance (TER) measurements monitored the barrier function of monolayer cultured RPE cells. The cells were treated with 0-100 µg/mL glycated BSA (a model AGE-product) from the apical side. BSA, 10 ng/mL VEGF, and 5 µM SU5416 were used as controls. Apical and basal VEGF production was determined from ELISA assays. The effects of glycated BSA on the integrity of the RPE were evaluated with intravitreal injections of rats followed by immunohistochemical staining of the RPE tight junctions.
Glycated BSA decreased the TER of RPE cells. The rapid time course of the induced TER decline was similar to the one caused by VEGF, and was also blocked by SU5416. The administration of glycated BSA selectively increased apical VEGF production from the RPE cells. Intraocular injection of both VEGF and glycated BSA reduced the integrity of tight junctional contacts between the RPE cells resulting in the appearance of 0.2-0.5 µM diameter holes between neighboring cell membranes. Vehicle treatment did not significantly change the structural integrity of the RPE.
These in vitro data provide evidence that AGE-products increase RPE monolayer permeability through VEGF secreted from the RPE because 1) SU5416 (a VEGF receptor inhibitor) blocked the AGE-respone; 2) apical VEGF production is induced by AGE-products; and 3) the VEGF-R2 receptors, responsible for the mediation of the VEGF-response, are located exclusively on the apical side of the RPE [Ablonczy and Crosson, Exp Eye Res, 2007]). The AGEs also disrupted the integrity of the RPE tight junctions inthe in vivo experiments. Therefore, the accumulation of intraocular AGE-products in diabetic retinopathy can impair RPE barrier function, thus contributing to the development of macular edema.
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