Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury.
Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury.
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DOI：
10.1254/jphs.cpj04005x
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发表时间：
2005
影响因子：
3.5
通讯作者：
H. Yonekura;Yasuhiko Yamamoto;S. Sakurai;Takuo Watanabe;Hiroshi Yamamoto
中科院分区：
文献类型：
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作者：
H. Yonekura;Yasuhiko Yamamoto;S. Sakurai;Takuo Watanabe;Hiroshi Yamamoto
糖尿病患者的寿命较短，生活质量较差，主要是由于糖尿病血管并发症。最近的体外和体内研究表明，晚期糖基化终末产物（AGE）通过其与AGE受体（AGEs）的结合而导致糖尿病血管并发症。本文就AGE-R系统在糖尿病血管损伤中的作用作一综述。体外实验表明，AGE参与糖尿病微血管病变导致内皮细胞（EC）和周细胞的变化，这是糖尿病微血管病变的特征。在血管细胞中过表达β-淀粉样蛋白的糖尿病β-淀粉样蛋白转基因小鼠表现出肾病和视网膜病变指数的恶化，并且通过抑制AGE形成来防止。过表达也引起心肌细胞钙处理障碍。与RAGE过表达小鼠相反，糖尿病RX 4基因敲除小鼠显示出肾病的显著改善。我们发现，人类血管细胞表达一种新的剪接变异体编码的可溶性β蛋白，并命名为内源性分泌型β蛋白（esophageal）。雌二醇中和AGE对EC的作用，并存在于人血清中。循环内皮素的个体差异可能是糖尿病血管并发症发生的易感性或抵抗力个体差异的决定因素。因此，AGE-E2系统应该是克服糖尿病血管并发症的候选分子靶点。
Diabetic patients have shorter life span and poorer Quality of Life mainly due to diabetic vascular complications. Recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vascular complications through their engagement of the receptor for AGE (RAGE). In this review, we summarize our recent studies on the roles of the AGE-RAGE system in diabetes-induced vascular injury. In vitro experiments showed that AGE engagement of RAGE leads to changes in endothelial cells (EC) and pericytes, which are characteristic of diabetic microangiopathy. Diabetic RAGE transgenic mice that overexpress RAGE in vascular cells exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. RAGE overexpression also caused calcium handling impairment in cardiac myocytes. In contrast to the RAGE-overexpressing mice, diabetic RAGE knockout mice showed marked improvement of nephropathy. We found that human vascular cells express a novel splice variant coding for a soluble RAGE protein and named it endogenous secretory RAGE (esRAGE). The esRAGE neutralizes AGE actions on EC and is present in human sera. Individual variations in circulating esRAGE could be a determinant for individual differences in susceptibility or resistance to the development of diabetic vascular complications. The AGE-RAGE system should be, therefore, a candidate molecular target for overcoming diabetic vascular complications.