Hori O, Yan S D, Ogawa S, Kuwabara K, Matsumoto M, Stern D, Schmidt A M
Department of Physiology, Columbia University College of Physician and Surgeons, New York, NY 10032, USA.
Nephrol Dial Transplant. 1996;11 Suppl 5:13-6. doi: 10.1093/ndt/11.supp5.13.
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.
暴露于醛糖的蛋白质或脂质会经历初始且最终不可逆的修饰，导致形成所谓的晚期糖基化终末产物（AGEs）。由于糖尿病的特征是高血糖，因此推测AGEs在糖尿病的情况下尤为重要。我们的研究表明，AGEs与血管壁相互作用的主要方式之一是与其细胞受体——晚期糖基化终末产物受体（RAGE）相互作用，RAGE存在于内皮细胞、平滑肌细胞、系膜细胞、单核吞噬细胞和某些神经元的表面。AGEs与RAGE相互作用，导致单核细胞趋化以及氧化应激的诱导。AGE-RAGE诱导的细胞氧化应激的后果之一是内皮表面血管细胞黏附分子-1的表达增强，其关键后果是单核吞噬细胞被吸引到血管壁中。在这两种情况下，使用抗RAGE F(ab')2或分子的细胞外结构域可溶性RAGE进行RAGE阻断时，AGEs的促炎作用可能会受到抑制。这些数据表明，抑制RAGE可能会干扰单核细胞趋化以及其向AGEs沉积/形成的血管壁中的吸引，提示这种干预措施有可能干扰血管疾病发展的关键步骤，尤其是在糖尿病患者中。
