December 2002
Volume 43, Issue 13
Free
ARVO Annual Meeting Abstract  |   December 2002
A Modulatory Role for Advanced Glycation End-Products (AGEs) in Retinal Microvascular Leukostasis
Author Affiliations & Notes
  • TB McMullen
    University of Ulster Coleraine School of Biomedical Sciences & Queen's University of Belfast United Kingdom
  • N Frizzell
    Ophthalmology Queen's University of Belfast United Kingdom
  • JE Moore
    Ophthalmology Queen's University of Belfast United Kingdom
  • V Poulaki
    Massachusetts Eye & Ear Infirmary Harvard Medical School MA
  • IL Campbell
    Scripps Research Institute CA
  • NA Afshari
    Massachusetts Eye & Ear Infirmary Harvard Medical School MA
  • Y Kaji
    Massachusetts Eye & Ear Infirmary Harvard Medical School MA
  • AW Stitt
    Ophthalmology Queen's University of Belfast United Kingdom
  • DB Archer
    Ophthalmology Queen's University of Belfast United Kingdom
  • AP Adamis
    Massachusetts Eye & Ear Infirmary Harvard Medical School MA
  • Footnotes
    Commercial Relationships   T.B. McMullen, None; N. Frizzell, None; J.E. Moore, None; V. Poulaki, None; I.L. Campbell, None; N.A. Afshari, None; Y. Kaji, None; A.W. Stitt, None; D.B. Archer, None; A.P. Adamis, None. Grant Identification: NIH EY 11627 & EY 12611 FIGHT FOR SIGHT & R&D
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 1348. doi:
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    • Get Citation

      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)

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Abstract

Abstract: : 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.

Keywords: 554 retina • 615 vascular occlusion/vascular occlusive disease • 614 vascular cells 
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