Increased Levels of Vascular Endothelial Growth Factor and Advanced Glycation End Products in Aqueous Humor of Patients With Diabetic Retinopathy

Abstract

Clinical studies have shown a relationship between diabetic retinopathy and vascular endothelial growth factor (VEGF) levels in ocular fluid. Advanced glycation end products (AGEs) have been implicated in diabetes complications, including diabetic retinopathy. Nepsilon-(carboxymethyl) lysine (CML) is a glycoxidation product that may be a marker of oxidative stress. In this study, we used enzyme-linked immunosorbent assays to determine the levels of VEGF, non-CML AGE and CML in the aqueous humor and serum of 82 Japanese patients with type 2 diabetes and 60 non-diabetic subjects. VEGF, non-CML AGE, and CML concentrations in aqueous humor and serum were then compared with the severity of diabetic retinopathy. Immunohistochemical detection analysis of non-CML AGE and CML was also performed using retinal tissues from patients with progressive diabetic retinopathy. Aqueous levels of VEGF, non-CML AGE and CML increased along with the progression of diabetic retinopathy compared to age-matched controls. After coagulation therapy, the VEGF, non-CML AGE, and CML levels were significantly reduced. Immunostaining showed diffuse co-localization of non-CML AGE and CML around microvessels and in the glial cells of proliferative membranes from patients with progressive diabetic retinopathy. These findings suggest that glycation and glycoxidation reactions (or oxidation, as revealed by CML) may contribute to both the onset and progression of diabetic retinopathy.

The role of vascular endothelial growth factor in the progression of diabetic vascular complications

“…They showed a highly significant reduction in the serum VEGF compared with their values before PRP performance (Table 7). These observations agreed with the findings of Lip et al, 49 Shinoda et al, 50 and Endo et al, 51 who detected a significant reduction in serum VEGF in a studied group of patients with PDR when performed effective PRP in 4 months follow-up.…”

“…In addition, PRP may cause ablation of many retinal cells capable of secreting VEGF such as retinal pigment epithelial ceils, pericytes, endothelial cells, Muller cells, and astrocytes. 37,51 …”

Immunolocalization of advanced glycation end products in human diabetic eyes: an immunohistochemical study

“…This immunohistochemical study showed that AGE immunoreactivity was detectable in the vitreous of diabetic eyes, suggesting that AGE can be secreted into intraocular fluid. In addition, Endo et al demonstrated that AGE concentration was increased in the aqueous humor in diabetic patients without retinopathy [11]. This study clearly demonstrated that AGE accumulation was marked in the iris and ciliary body stroma of diabetic eyes, indicating that the high concentration of AGE in the aqueous humor is related to the accumulated AGE in the iris and ciliary body.…”

“…High concentrations of AGE have been observed in the vitreous of patients with diabetic retinopathy [11,12,18]. This immunohistochemical study showed that AGE immunoreactivity was detectable in the vitreous of diabetic eyes, suggesting that AGE can be secreted into intraocular fluid.…”

“…The pathological crosslink formation induced by AGE usually affects the stable and long-lived proteins, leading to increased stiffness of the protein matrix and increased resistance to removal by proteolytic means [8][9][10]. In subsequent investigations, a high concentration of AGE was noted in the vitreous and aqueous humor in patients with diabetic retinopathy [11,12]. The increase in AGE colocalized with RAGE in the diabetic retina is correlated with the onset and progression of retinopathy [13].…”