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S.R. Tari, S.E. Lee, J.J. Tseng, D. Onat, S.I. Pachydaki, H. Hörig, D.N. Moroziewicz, S.F. Yan, A.M. Schmidt, G.R. Barile; Blockade of RAGE supresses hypoxia–induced Egr–1 expression in the retina . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1187.
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Purpose: Previous studies have suggested key roles for egr–1 in upregulation of inflammatory and prothrombotic genes in the cardiovascular system in hypoxia. Uprgulation of Egr–1 may lead to cellular dysfunction such as increased vascular permeability and induction of apoptosis cascades. This study sought to examine the effects of blockade of the proinflammatory receptor for advanced glycation end product (RAGE) axis upon hypoxia–induced Egr–1 expression in the retina. Methods: Twelve C57/blk6 mice were divided into four groups: 1) Untreated controls; 2) Treated controls administered two intraperitoneal doses of sRAGE (soluble receptor for advanced glycation end products, a competitive inhibitor for RAGE, injected 24 hours and 30 minutes prior to sacrifice); 3) Hypoxic mice placed in a chamber for 6 hours at 6–6.5% O2 concentration; and 4) Treated, hypoxic mice administered two doses of sRAGE as in the second group and placed in the hypoxia chamber simultaneously with the third group. Animals were immediately sacrificed, the eyes enucleated, and the retinas isolated and prepared for quantitative PCR analysis. One eye of each group was put in 4% paraformaldahyde for use in immunohistochemistry. Results: Quantitative gene analysis by real–time PCR showed a 4.3 fold elevation of Egr–1 mRNA levels, and this elevation was reversed by blockade of RAGE using sRAGE. Immunostaining for Egr–1 suggested zones of co–localization with RAGE in the inner retina. View OriginalDownload SlideView OriginalDownload Slide Conclusion: These findings suggest key roles for the RAGE–dependent mechanisms in regulation of egr–1 in hypoxic stress in the retina.
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