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K.A. Howes, Y. Liu, J.M. Frederick, W. Baehr; AGE (Advanced glycation end products) receptors in age–related macular degeneration . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2286.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Age–related macular degeneration is the leading cause of blindness in the elderly of industrialized nations. No current therapy can halt vision loss. In regions of amplifying oxidative stress, as occurs in aging disorders, advanced glycation end (AGE) product formation is accelerated. In many aging disorders including Alzheimer's disease, atherosclerosis, rheumatoid arthritis, and complications associated with diabetes, AGE products induce a receptor–mediated cellular response, activating expression of genes affecting growth, matrix organization, cell differentiation status, and apoptosis. In this study, AGE and cellular activating AGE receptors, RAGE and AGE–R2 are examined in aging and AMD eyes as factors contributing to disease progression. Methods: Nonexudative AMD and age matched control eyes were assayed for RAGE and AGE–R2 expression using immunocytochemistry. ARPE–19 (RPE) cell cultures were used to directly assess intracellular signalling and specific expression of genes altered by AGE product and S100B (another RAGE ligand) treatments. Microarray analysis of altered gene expression is used to identify genes directly responding to AGE and S100B treatments. Results: RAGE and AGE–R2 expression, assayed with immunocytochemistry, is upregulated in the retinal pigment epithelium (RPE) of AMD tissues and in normal eyes associated with regions of early histopathology such as drusen formation. ARPE–19 cells treated with AGE and S100B induce NFkappaB nuclear translocation, RAGE and AGE–R2 upregulation and apoptosis, all of which are known events mediated by RAGE ligand treatments. Expression of genes directly altered by RAGE ligands is currently being assayed by microarray analysis. Conclusions: AGE products induce RPE cellular activation through RAGE and AGE–R2 as assessed through RPE cell assay and observed upregulation of expression in AMD and normal eyes showing classic histopathological features. These data support a causal role for AGE receptors in disease progression, similar to other aging disorders, in the aging eye leading to AMD.
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