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

共 67 条

[1] Human RPE cells express the FGFR2IIIc and FGFR3IIIc splice variants and FGF9 as a potential high affinity ligand [J].

Alizadeh, M ;

Miyamura, N ;

Handa, JT ;

Hjelmeland, LM .

EXPERIMENTAL EYE RESEARCH, 2003, 76 (02) :249-256

[2] Regulation of cysteine cathepsin expression by oxidative stress in the retinal pigment epithelium/choroid of the mouse [J].

Alizadeh, Parvaneh ;

Smit-McBride, Zeljka ;

Oltjen, Sharon L. ;

Hjelmeland, Leonard M. .

EXPERIMENTAL EYE RESEARCH, 2006, 83 (03) :679-687

[3] The role of AGEs in aging: causation or correlation [J].

Baynes, JW .

EXPERIMENTAL GERONTOLOGY, 2001, 36 (09) :1527-1537

[4] REGIONAL VARIATION AND AGE-RELATED-CHANGES OF LYSOSOMAL-ENZYMES IN THE HUMAN RETINAL-PIGMENT EPITHELIUM [J].

BOULTON, M ;

MORIARTY, P ;

JARVISEVANS, J ;

MARCYNIUK, B .

BRITISH JOURNAL OF OPHTHALMOLOGY, 1994, 78 (02) :125-129

[5]

Cai H, 2006, MOL VIS, V12, P1

[6] Age-related changes of glycosidases in human retinal pigment epithelium [J].

Cingle, KA ;

Kalski, RS ;

Bruner, WE ;

OBrien, CM ;

Erhard, P ;

Wyszynski, RE .

CURRENT EYE RESEARCH, 1996, 15 (04) :433-438

[7] THE PREVALENCE OF MACULAR DRUSEN IN POSTMORTEM EYES [J].

COFFEY, AJH ;

BROWNSTEIN, S .

AMERICAN JOURNAL OF OPHTHALMOLOGY, 1986, 102 (02) :164-171

[8] ARPE-19, a human retinal pigment epithelial cell line with differentiated properties [J].

Dunn, KC ;

AotakiKeen, AE ;

Putkey, FR ;

Hjelmeland, LM .

EXPERIMENTAL EYE RESEARCH, 1996, 62 (02) :155-169

[9] Role of vascular endothelial growth factor and placental growth factors during retinal vascular development and hyaloid regression [J].

Feeney, SA ;

Simpson, DAC ;

Gardiner, TA ;

Boyle, C ;

Jamison, P ;

Stitt, AW .

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2003, 44 (02) :839-847

[10]

Garg Tarun K., 2004, BMC Pharmacology, V4, P6, DOI 10.1186/1471-2210-4-6

← 1 2 3 4 5 6 7 →