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TB McMullen, N Frizzell, JE Moore, V Poulaki, IL Campbell, NA Afshari, Y Kaji, AW Stitt, DB Archer, AP Adamis; A Modulatory Role for Advanced Glycation End-Products (AGEs) in Retinal Microvascular Leukostasis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1348.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:A critical early event in the pathogenesis of diabetic retinopathy is the inappropriate adherence of leukocytes to the retinal vasculature. AGEs are known to play a role in chronic inflammatory processes and we postulated that these adducts may play a role in promoting pathogenic increases in pro-inflammatory pathways within the retinal microvasculature. Methods: Retinal microvascular endothelial cells (RMECs) were treated with glycoaldehyde-modified albumin (AGE-Alb) or unmodified Alb. ICAM-1 protein expression was visualised using immunocytochemical methods. Downstream activation of NFkB was monitored using EMSA and quantified using ELISA. In addition, the effect of AGEs on leukocyte adhesion to endothelial cell monolayers was investigated. Parallel in vivo studies using non-diabetic mice assessed the effect of intra-peritoneal delivery of AGE-Alb on ICAM-1 mRNA expression, NFkB DNA binding activity, leukostasis and blood retinal barrier breakdown. Results: AGE-Alb exposure significantly increased expression of ICAM-1 in RMECs and demonstrated enhanced NFkB DNA binding activity (p=0.0045). Stimulation of RMECs to AGE-Alb caused increased adhesion of leukocytes to RMEC monolayers (p=0.04). Mice infused with AGE-Alb demonstrated a 1.8 fold increase in ICAM-1 mRNA compared to control ALb infused mice (p<0.001, n=20 mice) as early as 48 hours and remained for the 7 days of treatment. Quantification of retinal NFkB demonstrated a 3 fold increase with AGE-Alb infusion in comparison to controls (AGE-Alb vs. Alb, 0.23 vs. 0.076, n=10 mice p<0.001). AGE-Alb treatment also caused a significant breakdown of the inner blood retinal barrier (AGE-Alb vs. Alb, 8.2 vs. 1.6, n=10 mice, p<0.001). Conclusion: AGEs cause upregulation of ICAM-1 in the retinal microvascular endothelium, possibly via NFkB activation. This was accompanied by increased leukocyte adherence and blood retinal barrier dysfunction. These data add further evidence that AGEs may play an important role in the pathogenesis of diabetic retinopathy.
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