Possible participation of advanced glycation endproducts and their receptor system in the development of diabetic vascular complications

Abstract

Diabetes causes vascular injuries in various organs and tissues, among which the lesions in retina and kidney are called retinopathy and nephropathy, respectively. As the number of diabetic patients is increasing in Japan, the population with the vascular complications is also elevating. For preventing diabetic complications, it is necessary to develop new drugs that target for key molecules in the development of this disease and useful animal models for the evaluation of their therapeutic potentials. We have focused on the non-enzymatic glycation reaction under prolonged hyperglycemia, which results in the formation and accumulation of advanced glycation endproducts (AGE). The interaction of AGE with the receptor for AGE (RAGE) has been implicated in the development of the vascular complications. AGE elicited vascular cell changes typical of diabetes, including angiogenic and thrombogenic responses of endothelial cells (EC), and a decrease in pericytes, the hallmarks of diabetic retinopathy. Our recent in vivo study revealed that transgenic mice overexpressing human RAGE in vascular EC developed advanced nephropathy when they were made diabetic. This mouse is thus regarded as a useful animal model of diabetic vascular disease. These results suggest that the AGE-RAGE system plays an active role in the development of diabetic vasculopathy and is a promising target in the prophylaxis and therapy of this disease. Recently, we identified three RAGE variants: novel C-terminally and N-terminally truncated forms and the known full-length form. The C-terminally truncated variant was found to be a soluble form and actually detected in human sera, and it was found to have neutralizing activities against AGE-induced EC injury. The endogenous soluble decoy against the AGE-RAGE system may contribute to the individual resistance to the development of diabetic vascular complications. The stimulation of secretion of this protein can be a new means for the prevention of chronic vascular disease in diabetes.