RAGE engagement and vascular cell derangement by short chain sugar-derived advanced glycation end products

Abstract We have previously shown that engagement by advanced glycation end products (AGE) of the receptor for AGE (RAGE) leads to endothelial cell (EC) and pericyte deterioration characteristic of diabetic vasculopaphy. Recently, AGE have been shown to be generated not only from glucose but also from short chain aldehydes. We examined the ability of these new AGE fractions to bind RAGE and to affect human vascular cells. Purified human endogenous soluble RAGE was coupled to a sensor chip of a BIAcore surface plasmon resonance system, onto which each AGE fraction was applied. This assay demonstrated that out of six distinct AGE fractions, AGE 1, 2 and 3 derived from glucose, glyceraldehyde and glycolaldehyde, respectively, bound to RAGE, and that AGE 2 and 3 had higher binding activity than AGE 1. The binding of 125 I-labeled AGE 2 and 3 on RAGE-overexpressing COS-7 cells was also detected with K d values similar to those disclosed by the BIAcore assay. The AGE fractions increased VEGF mRNA levels in human endothelial cells as well as the viable cell number and DNA synthesis. AGE 2 and 3 significantly decreased pericyte synthesis of DNA at lower concentrations than AGE 1. These results indicated that AGE 2 and 3 are new RAGE ligands and, which may participate in vascular injury in diabetes.