Advanced glycation end products, their receptors and diabetic angiopathy

The role of chronic hyperglycemia in the development of diabetic microvascu lar complications and in neuropathy has been clearly established by interve ntion studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understo od. This review focuses on the consequences of hyperglycemia on the formati on of advanced glycation end-products (AGEs), and on the role of AGEs and o f their specific receptors (RAGE) in the functional and anatomical alterati ons of the vascular wall. AGEs are formed during the Mailiard reaction by t he binding of aldoses on free NH2 groups of proteins, which, after a cascad e of molecular rearrangements, result in molecules of brown color and speci fic fluorescence. Experimental studies have indicated that the binding of A GEs to RAGE activates cells, particularly monocytes and endothelial calls. Activated endothelial cells produce cytokines, and express adhesion molecul es and tissue factor. The role of AGEs in increased oxidative stress, and i n the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The mic rovascular retinal, glomerular and nerve lesions induced by experimental di abetes in animals are prevented by an inhibitor of AGEs formation, aminogua nidine. The administration in diabetic animals of recombinant RAGE, which h inders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesio ns. These data suggest a central role of AGEs and RAGE in the development o f chronic complications of diabetes.