Receptor mediated disruption of retinal pigment epithelium function in acute glycated-albumin exposure

- A model of diabetic eye disease using glycated-albumin (Glyc-alb) in DB rabbits and fhRPE cells.
- Assessment of RPE function in vivo using kinetics of subretinal fluid resorption.
- Glyc-alb decreases subretinal fluid resorption 48 h post intravitreal injection.
- Glyc-alb response is mediated by RAGE and VEGF-R2 in vivo and in vitro.
- The RAGE receptors are localized on the apical surface of the RPE cells.

Diabetic macular edema (DME) is a major cause of visual impairment. Although DME is generally believed to be a microvascular disease, dysfunction of the retinal pigment epithelium (RPE) can also contribute to its development. Advanced glycation end-products (AGE) are thought to be one of the key factors involved in the pathogenesis of diabetes in the eye, and we have previously demonstrated a rapid breakdown of RPE function following glycated-albumin (Glyc-alb, a common AGE mimetic) administration in monolayer cultures of fetal human RPE cells. Here we present new evidence that this response is attributed to apically oriented AGE receptors (RAGE). Moreover, time-lapse optical coherence tomography in Dutch-belted rabbits 48 h post intravitreal Glyc-alb injections demonstrated a significant decrease in RPE-mediated fluid resorption in vivo. In both the animal and tissue culture models, the response to Glyc-alb was blocked by the relatively selective RAGE antagonist, FPS-ZM1 and was also inhibited by ZM323881, a relatively selective vascular endothelial growth factor receptor 2 (VEGF-R2) antagonist. Our data establish that the Glyc-alb-induced breakdown of RPE function is mediated via specific RAGE and VEGF-R2 signaling both in vitro and in vivo. These results are consistent with the notion that the RPE is a key player in the pathogenesis of DME.

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