|Budget Amount *help
¥2,600,000 (Direct Cost : ¥2,600,000)
Fiscal Year 1998 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1997 : ¥1,900,000 (Direct Cost : ¥1,900,000)
Vascular endothelial growth factor (VEGF) has been causally linked to many changes including retinal edema, hemorrahge, ischemia, microaneurysm, and neovascularization that are characterized diabetic retinopathy. Hypoxia is considered a functional stimulus for VEGF expression in the diabetic eye. However, the mechanisms of hypoxia-induced VEGE expression is still unknown. We have reported that reactive oxygene intermediates (ROI), superoxide and hydrogen peroxide, increases the VEGF gene expression. Therfore, first in this study, we studied the involvement of oxidative stress in the hypoxia-induced VEGF gene expression. Antioxidant agents inhibited the VEGF expression induced by hypoxia and ROI was suggested to be generated through the activation of the archidonic acid pathway.
VEGF has been reported to be recognized in the retina of eary stage of diabetic retinopathy. Therefore, beside the hypoxia, other stimui also may be operative.
Advanced glycation end products (AGEs) have a causal
role in the development of diabetic complications and correlate with the onset and severity of retinopathy. AGEs were immunohistochemically detected in the retina, proliferative fibromuscular tissues and iris of diabetic patients, and the concentration of AGEs which was estimated with ELBA significantly increased in the vitreous humor of diabetic patients in comparison with those of normal subjects. Based on these data, we examined the role of AGEs in the induction of retinal gene expression. In vitro, AGEs increased VEGF mRNA and protein in human retinal pigment epithelial cells (RPE) and smooth muscle cells (SMC). AGE-induced increases in VEGF were inhibited by antioxidants. In vivo, AGEs increased VEGF mRNA levels in the rat retina. Clinical observations and laboratory data indicate a pathological link between intraocular neovascularization and insulin-like growth factor-i (IGF-1) which has been reported to be increased in daibetic eye. Our study showed tha IGF-1 increased VEGF mRNA levels through the enhancement of VEGF promotor activity in RPE and SMC.Oxidazed low density lipoprotein (oxLDL) was believed to have a major role of the vascular injury and to be increased in the daibetic condition. Our study showed that lysoposphatidylchoilne (LPC) which is the main component of oxLDL increased VEGF mRNa levels and LPC-induced increase in VEGF were inhibited by antioxidants. These results indicate that elevated AGEs, JGF-1 and oxLDL levels may promote retinal neovascularization in diabetes through increased retinal VEGF gene expression.
Our results in this study showed that VEGF gene expression induced by hypoxia, AGEs and oxLDL is regulated by the intracelluar oxidative stress. Recently nitric oxide (NO) has been reported to prevent the several action of ROL.Our study showed that NO inhibited the VEGF gene expression induced by hypoxia and AGES.This suggests that the nitrites which are used widely may be useful for the treatment of diabetic retinopathy. Less