Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats.
Advanced glycation end products (AGEs) have been implicated in the progressive vascular dysfunction which occurs during diabetic retinopathy. In the current study we have examined the role of these adducts in blood-retinal barrier (BRB) breakdown and investigated expression of the vasopermeabilizing agent vascular endothelial growth factor (VEGF) in the retina. When normoglycemic rats were injected with AGE-modified albumin daily for up to 10 days there was widespread leakage of FITC-dextran and serum albumin from the retinal vasculature when compared to control animals treated with nonmodified albumin. Ultrastructural examination of the vasculature revealed areas of attenuation of the retinal vascular endothelium and increased vesicular organelles only in the AGE-exposed rats. Quantitative RT-PCR and in situ hybridization demonstrated a significant increase in retinal VEGF mRNA expression (P < 0.05). These results suggest that AGEs can initiate BRB dysfunction in nondiabetic rats and a concomitant increase in retinal VEGF expression. These findings may have implications for the role of AGEs in the pathogenesis of diabetic retinopathy.
Stitt
A W
AW
Department of Ophthalmology, Queen's University of Belfast, Northern Ireland, United Kingdom.
Bhaduri
T
T
McMullen
C B
CB
Gardiner
T A
TA
Archer
D B
DB
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000502:physiology; D015139:Blotting, Southern; D002199:Capillary Permeability / Q000187:drug effects; D021941:Caveolae / Q000648:ultrastructure; D003911:Dextrans; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000503:physiopathology*; D016228:Endothelial Growth Factors / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017403:In Situ Hybridization; D008222:Lymphokines / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D003911:Dextrans; D016228:Endothelial Growth Factors; D017127:Glycation End Products, Advanced; D008222:Lymphokines; D012333:RNA, Messenger; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate