ADVANCED GLYCATION END-PRODUCTS (AGES) ON THE SURFACE OF DIABETIC ERYTHROCYTES BIND TO THE VESSEL WALL VIA A SPECIFIC RECEPTOR INDUCING OXIDANT STRESS IN THE VASCULATURE - A LINK BETWEEN SURFACE-ASSOCIATED AGES AND DIABETIC COMPLICATIONS

Vascular complications are an important cause of morbidity and mortali ty in patients with diabetes. The extent of vascular complications has been linked statistically to enhanced adherence of diabetic erythrocy tes to endothelial cells (ECs) and to the accumulation of a class of g lycated proteins termed advanced glycation end products (AGEs). We hyp othesized that formation of AGEs on the surface of diabetic erythrocyt es could mediate their interaction with ECs leading to binding and ind uction of vascular dysfunction. Enhanced binding of diabetic erythrocy tes to ECs was blocked by preincubation of erythrocytes with anti-AGE IgG or preincubation of ECs with antibodies to the receptor for AGE (R AGE). Immunoblotting of cultured human ECs and immunostaining of norma l/diabetic human tissue confirmed the presence of RAGE is the vessel w all. Binding of diabetic erythrocytes to endothelium generated an oxid ant stress, as measured by production of thiobarbituric acid-reactive substances (TEARS) and activation of the transcription factor NF-kappa B, both of which were blocked by probucol or anti-RAGE IgG. Erythrocy tes from diabetic rats infused into normal rats had an accelerated, ea rly phase of clearance that was prevented, in part, by antibody to RAG E. Liver tissue from rats infused with diabetic erythrocytes showed el evated levels of TBARS, which was prevented by pretreatment with anti- RAGE IgG or probucol. Thus, erythrocyte surface AGEs can function as l igands that interact with RAGE on endothelium. The extensive contact o f diabetic erythrocytes bearing surface-associated AGEs with vessel wa ll RAGE could be important in the development of vascular complication s.