Involvement of TAGE-RAGE System in the Pathogenesis of Diabetic Retinopathy

Abstract

Diabetic complications are a leading cause of acquired blindness, end-stage renal failure, and accelerated atherosclerosis, which are associated with the disabilities and high mortality rates seen in diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, recent evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications. In this paper, we discuss the pathophysiological role of the TAGE-RAGE system in the development and progression of diabetic retinopathy.

Figure 1

Alternative routes for the formation of various distinct AGEs in vivo. Glc-AGEs; glucose-derived AGEs, Glycer-AGEs; glyceraldehyde-derived AGEs, Glycol-AGEs; glycolaldehyde-derived AGEs, MGO-AGEs; methylglyoxal (MGO)-derived AGEs, GO-AGEs; glyoxal (GO)-derived AGEs, and 3-DG-AGEs, 3-deoxyglucosone (3-DG)-derived AGEs, CML; N-(carboxymethyl)lysine, and P-NH₂; free amino residue of protein.

Figure 2

Production routes of glyceraldehyde-derived AGEs (Glycer-AGEs) in vivo. TAGE; toxic AGEs (glyceraldehyde-derived AGEs), RAGE; receptor for AGEs, ROS; reactive oxygen species, HFCS; high-fructose corn syrup, AR; aldose reductase, SDH; sorbitol dehydrogenase, FK; fructokinase, GAPDH; glyceraldehyde-3-phosphate dehydrogenase, ∗; TAGE.