Advanced Glycation End Product (AGE) Accumulation on Bruch's Membrane: Links to Age-Related RPE Dysfunction

被引：76

作者：

Glenn, Josephine V. ^{[1
]}

Mahaffy, Helen ^{[1
]}

Wu, Keqiang ^{[2
]}

Smith, Gill ^{[2
]}

Nagai, Ryoji ^{[3
]}

Simpson, David A. C. ^{[1
]}

Boulton, Michael E. ^{[2
,4
]}

Stitt, Alan W. ^{[1
]}

机构：

[1] Queens Univ Belfast, Sch Med Dent & BioMed Sci, Ctr Vis & Vasc Sci, Belfast BT12 6BA, Antrim, North Ireland

[2] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL USA

[3] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Biochem Med, Kumamoto, Japan

[4] Cardiff Univ, Sch Optometry & Visual Sci, Cardiff, S Glam, Wales

来源：

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE | 2009年 / 50卷 / 01期

基金：

英国惠康基金;

关键词：

RETINAL-PIGMENT EPITHELIUM; GENE-EXPRESSION PROFILE; ROD OUTER SEGMENTS; MACULAR DEGENERATION; OXIDATIVE STRESS; CATHEPSIN-D; EXTRACELLULAR-MATRIX; ARPE-19; CELLS; GROWTH-FACTOR; PROTEINS;

D O I：

10.1167/iovs.08-1724

中图分类号：

R77 [眼科学];

学科分类号：

100212 ;

摘要：

PURPOSE. Advanced glycation end products (AGEs) accumulate during aging and have been observed in postmortem eyes within the retinal pigment epithelium (RPE), Bruch's membrane, and subcellular deposits ( drusen). AGEs have been associated with age-related dysfunction of the RPE-in particular with development and progression to age-related macular degeneration (AMD). In the present study the impact of AGEs at the RPE-Bruch's membrane interface was evaluated, to establish how these modifications may contribute to age-related disease. METHODS. AGEs on Bruch's membrane were evaluated using immunohistochemistry. A clinically relevant in vitro model of substrate AGE accumulation was established to mimic Bruch's membrane ageing. Responses of ARPE-19 growing on AGE-modified basement membrane (AGE-BM) for 1 month were investigated by using a microarray approach and validated by quantitative (q)RT-PCR. In addition to identified AGE-related mRNA alterations, lysosomal enzyme activity and lipofuscin accumulation were also studied in ARPE-19 grown on AGE-BM. RESULTS. Autofluorescent and glycolaldehyde-derived AGEs were observed in clinical specimens on Bruch's membrane and choroidal extracellular matrix. In vitro analysis identified a range of dysregulated mRNAs in ARPE-19 exposed to AGE-BM. Altered ARPE-19 degradative enzyme mRNA expression was observed on exposure to AGE-BM. AGE- BM caused a significant reduction in cathepsin-D activity in ARPE-19 (P < 0.05) and an increase in lipofuscin accumulation (P < 0.01). CONCLUSIONS. AGEs influence ARPE-19 mRNA expression profiles and may contribute to reduced lysosomal enzyme degradative capacity and enhanced accumulation of lipofuscin. Formation of AGEs on Bruch's membrane may have important consequences for age-related outer retinal disease. (Invest Ophthalmol Vis Sci. 2009; 50: 441-451) DOI:10.1167/iovs.08-1724

引用

页码：441 / 451

页数：11

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