title: Receptor mediated disruption of retinal pigment epithelium function in acute glycated-albumin exposure.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Dahrouj
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425, United States.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Desjardins
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425, United States.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425, United States.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425, United States. Electronic address: ablonczy@musc.edu.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ablonczy
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier; D002102:Cadaver; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008269:Macular Edema / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D011817:Rabbits; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D012709:Serum Albumin / Q000633:toxicity; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000093423:Glycated Serum Albumin
chemical_list: D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000093423:Glycated Serum Albumin
keywords: AGE; Barrier; DME; Diabetes; RPE; Rabbit; Retinopathy; VEGF