THE RECEPTOR FOR ADVANCED GLYCATION END-PRODUCTS HAS A CENTRAL ROLE IN MEDIATING THE EFFECTS OF ADVANCED GLYCATION END-PRODUCTS ON THE DEVELOPMENT OF VASCULAR-DISEASE IN DIABETES-MELLITUS

Proteins or lipids exposed to aldose sugars undergo initial and ultima tely irreversible modification resulting in the formation of so-called advanced glycation end-products (AGEs). AGEs are postulated to be esp ecially important in the setting of diabetes mellitus due to hyperglyc aemia characteristic of this disorder. Our work has demonstrated that one of the principal means by which AGEs interact with the vascular wa ll is by interaction with their cellular receptor, the receptor for ad vanced glycation end-products (RAGE), which is present on the surface of endothelial cells, smooth muscle cells, mesangial cells, mononuclea r phagocytes and certain neurons. AGEs interact with RAGE, resulting i n the induction of monocyte chemotaxis as well as oxidant stress. One of the consequences of AGE-RAGE-induced cellular oxidant stress is the enhanced expression of vascular cell adhesion molecule-1 on the endot helial surface, a critical consequence of which is the attraction of m ononuclear phagocytes into the vessel wall. In both cases, the pro-inf lammatory effects of AGEs may be inhibited in the presence of RACE blo ckade, using either anti-RAGE F(ab')(2) or soluble RAGE, the extracell ular domain of the molecule. These data suggest that inhibition of RAG E may interfere with monocyte chemotaxis and attraction into the vesse l wall where AGEs deposit/form, suggesting the potential of this inter vention to interfere with a critical step in the development of vascul ar disease, especially in patients with diabetes.