Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response

doi:10.1073/pnas.0504759102

Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response

^*Michael Panitch Macular Degeneration Laboratory, Wilmer Eye Institute, and ^‡Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and ^†Department of Neurosurgery, University of California, Davis, CA 95616

Communicated by Paul Talalay, Johns Hopkins University School of Medicine, Baltimore, MD, June 7, 2005 (received for review November 28, 2004)

Abstract

Advanced glycation endproduct (AGE) formation is a trigger for the onset of age-related disease. To evaluate AGE-induced change in the ocular fundus, 5-mo-old C57BL/6 mice were given low-dose d-galactose (d-gal) for 8 wk and evaluated by AGE fluorescence, electroretinography (ERG), electron microscopy, and microarray analysis for 20 wk. Although AGE fluorescence was increased in d-gal-treated retinal pigment epithelium (RPE)–choroid compared with controls at all time points, ERG showed no AGE-induced functional toxicity. Progressive ultrastructural aging in the RPE–choroid was associated temporally with a transcriptional response of early inflammation, matrix expansion, and aberrant lipid processing and, later, down-regulation of energy metabolism genes, up-regulation of crystallin genes, and altered expression of cell structure genes. The overall transcriptome is similar to the generalized aging response of unrelated cell types. A subset of transcriptional changes is similar to early atherosclerosis, a chronic inflammatory disease characterized by matrix expansion and lipid deposition. These changes suggest an important contribution of a single environmental stimulus to the complex aging response.

Footnotes

↵ § To whom correspondence should be addressed at: Johns Hopkins Medical Institutions, 3-109 Jefferson Street Building, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: jthanda{at}jhmi.edu.
Author contributions: P.G. and J.T.H. designed research; J.T., Kazuki Ishibashi, Kazuko Ishibashi, K.R., R.G., S.B., P.G., and J.T.H. performed research; K.R. contributed new reagents/analytic tools; J.T., Kazuki Ishibashi, K.R., R.G., S.B., P.G., and J.T.H. analyzed data; and J.T., Kazuki Ishibashi, P.G., and J.T.H. wrote the paper.
Abbreviations: AGE, advanced glycation endproduct; RPE, retinal pigment epithelium; d-gal, d-galactose; BM, Bruch's membrane; AMD, age-related macular degeneration; ECM, extracellular matrix; ex, excitation; em, emission; LPL, lipoprotein lipase; FABP, fatty acid-binding protein.
Freely available online through the PNAS open access option.