Role of Advanced Glycation End Products and Vascular Endothelial Growth Factor in Pathophysiology of Diabetic Retinopathy

Background: The hyperglycemic state occurring in diabetes mellitus is responsible
for formation and accumulation of advanced glycation end products (AGEs) that
participate with their receptors, receptor for advanced glycation end products (RAGE
) in the pathogenesis of vascular complications of diabetes mellitus. Intraocular
vascular endothelial growth factor (VEGF) levels have been studied in animal models
and human vitreous fluid, where the levels are found to be high in patients with active
intraocular neovascularization. Objective: To investigate the levels of AGEs ,soluble
form of RAGE (sRAGE) ,VEGF and total antioxidants (TAO) in both vitreous and
blood of diabetic patients with and without diabetic retinopathy. Study Design:
Blood and vitreous samples were collected from 30 diabetic patients, 15 with
proliferative diabetic retinopathy (PDR), 15 without retinopathy, and 15 non diabetic
control subjects. ELISA technique was used for measuring vitreous and blood levels
of AGE, sRAGE, VEGF and TAO. Results: AGEs, sRAGE and VEGF levels in blood
were significantly higher in all diabetic groups compared to controls and in PDR
patients compared to diabetic group. There were positive correlations between serum
AGEs, sRAGE and VEGF levels in both diabetic groups. Vitreous levels of AGEs and
VEGF were significantly increased in all diabetic groups compared to controls and in
PDR group compared to diabetic group. Also there were significant correlations
between these levels in both PDR and diabetic groups. Serum and vitreous TAO levels
were decreased in patients with diabetes compared to controls and in patients with
PDR compared to diabetics without retinopathy. Furthermore, Serum TAO levels
were inversely correlated with serum levels of AGEs, sRAGE and VEGF in all
diabetic patients. TAO levels in vitreous were inversely correlated with vitreous levels
of AGEs, and VEGF in all diabetic patients. Conclusion: These findings suggest that
the interaction of advanced glycation end products (AGEs), with their cellular
receptor (RAGE) and oxidative stress is implicated in the pathogenesis of diabetic
vascular complications through stimulation of VEGF.