Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: a comprehensive transcriptional response.
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.
Tian
Jane
J
Michael Panitch Macular Degeneration Laboratory, Wilmer Eye Institute, Baltimore, MD 21287, USA.
Ishibashi
Kazuki
K
Ishibashi
Kazuko
K
Reiser
Karen
K
Grebe
Rhonda
R
Biswal
Shyam
S
Gehlbach
Peter
P
Handa
James T
JT
D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D002829:Choroid / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005690:Galactose / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D005690:Galactose