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 ultimately irreversible modification resulting in the formation of so-called advanced glycation end-products (AGEs). AGEs are postulated to be especially important in the setting of diabetes mellitus due to hyperglycaemia characteristic of this disorder. Our work has demonstrated that one of the principal means by which AGEs interact with the vascular wall is by interaction with their cellular receptor, the receptor for advanced glycation end-products (RAGE), which is present on the surface of endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. AGEs interact with RAGE, resulting in 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 endothelial surface, a critical consequence of which is the attraction of mononuclear phagocytes into the vessel wall. In both cases, the pro-inflammatory effects of AGEs may be inhibited in the presence of RAGE blockade, using either anti-RAGE F(ab')2 or soluble RAGE, the extracellular domain of the molecule. These data suggest that inhibition of RAGE may interfere with monocyte chemotaxis and attraction into the vessel wall where AGEs deposit/form, suggesting the potential of this intervention to interfere with a critical step in the development of vascular disease, especially in patients with diabetes.
Hori
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Department of Physiology, Columbia University College of Physician and Surgeons, New York, NY 10032, USA.
Yan
S D
SD
Ogawa
S
S
Kuwabara
K
K
Matsumoto
M
M
Stern
D
D
Schmidt
A M
AM
D000818:Animals; D002634:Chemotaxis, Leukocyte; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D010586:Phagocytes / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1