Advanced glycation end products increase retinal vascular endothelial growth factor expression.
Advanced glycation end products (AGEs) are linked with the development of diabetic retinopathy; however, the pathogenic mechanisms are poorly defined. Vascular endothelial growth factor (VEGF) levels are increased in ischemic and nonischemic diabetic retina, and VEGF is required for the development of retinal and iris neovascularization. Moreover, VEGF alone can induce much of the concomitant pathology of diabetic retinopathy. In this study, we found that AGEs increased VEGF mRNA levels in the ganglion, inner nuclear, and retinal pigment epithelial (RPE) cell layers of the rat retina. In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells. The AGE-induced increases in VEGF expression were dose- and time-dependent, inhibited by antioxidants, and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation induced by the conditioned media of AGE-treated cells. AGEs may participate in the pathogenesis of diabetic retinopathy through their ability to increase retinal VEGF gene expression.
Lu
M
M
Laboratory for Surgical Research, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kuroki
M
M
Amano
S
S
Tolentino
M
M
Keough
K
K
Kim
I
I
Bucala
R
R
Adamis
A P
AP
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000975:Antioxidants / Q000494:pharmacology; D015152:Blotting, Northern; D002417:Cattle; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D017403:In Situ Hybridization; D008222:Lymphokines / Q000032:analysis* / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism; D012260:Ribonucleases / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D019138:Antibodies, Blocking; D000975:Antioxidants; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D017127:Glycation End Products, Advanced; D008222:Lymphokines; D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; D012260:Ribonucleases