Nε-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression
Nε-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression
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DOI：
10.1074/jbc.274.44.31740
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发表时间：
1999-10-29
影响因子：
4.8
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Kislinger, T;Fu, CF;Schmidt, AM
最近的研究表明，通过施用 RAGE 的可溶性细胞外配体结合结构域，可以中断晚期糖基化终末产物 (AGE) 与 AGE 信号转导受体 (RAGE) 的相互作用，从而逆转糖尿病啮齿动物的血管通透性过高并抑制加速的动脉粥样硬化。由于在这些情况下可溶性 RAGE 的精确分子靶点尚未阐明，我们测试了这样的假设：糖尿病和肾衰竭等疾病的组织内主要的特异性 AGE，即 N-ε-(羧甲基)赖氨酸 (CML) 加合物，是 RAGE 的配体。我们在此证明，与生理相关的 CML 蛋白质修饰会参与细胞 RAGE，从而激活关键细胞信号传导途径（例如 NF-KB）并调节基因表达。因此，CML-RAGE 相互作用触发与加速血管和炎症并发症密切相关的过程，这些并发症是炎症是其中一个既定组成部分的典型疾病。
Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N-epsilon-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-KB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.