Soluble Receptor for AGEs in diabetes, platelet activation and atherosclerosis

AGEs受体(RAGE)参与糖尿病的大血管和微血管并发症。RAGE是一种细胞表面受体，属于免疫球蛋白超家族。AGEs与RAGE结合可激活细胞内信号转导通路，其中包括核因子-KB的激活。对RAGE过度表达和基因敲除小鼠的表型分析表明，RAGE与糖尿病肾病的进展密切相关。此外，RAGE在糖尿病动物的动脉粥样硬化斑块中表达上调，糖尿病小鼠动脉粥样硬化的加剧受到RAGE竞争的抑制。我们还表明RAGE参与了糖尿病血管生成反应的损害，这与缺血后严重程度的加速有关。内源性分泌型RAGE(EsRAGE)是一种新的剪接变异体，它携带所有的胞外区，但不包括跨膜区和胞内区。EsRAGE从细胞外释放，并在人血浆中检测到。糖尿病和高血压患者的血浆esRAGE显著降低。值得注意的是，血浆esRAGE与代谢综合征的成分显著负相关，包括体重指数、甘油三酯或胰岛素抵抗指数。在一组终末期肾脏疾病(ESRD)中，血浆esRAGE最低三分位数的受试者心血管死亡的累积发生率显著较高，与糖尿病的存在无关。此外，在小鼠体内过表达esRAGE的腺病毒显著恢复了糖尿病患者的血管功能障碍。因此，我们推测血浆esRAGE是一种潜在的保护因子和一种新的抗动脉粥样硬化和代谢综合征的生物标志物。

Receptor for AGEs (RAGE) is involved in macro- and microvascular complications in diabetes. RAGE is a cell surface receptor belongs to the immunoglobulin superfamily. Ligation of AGEs with RAGE results in activation of cellular signaling pathway including NF-KB activation. Analyses of the phenotypes of RAGE-overexpressing and -knockout mice revealed that RAGE is deeply involved in progression of diabetic nephropathy. Moreover, RAGE expression is upregulated in atherosclerotic plaques of diabetic animals, and augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE. We have also shown that RAGE is involved in diabetes impairment of angiogenic response, which is implicated in acceleration of severity following ischemia. An endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains. esRAGE is released outside from the cells, and is detected in human plasma. Plasma esRAGE is significantly lower in patients with diabetes and hypertension. Of note, plasma esRAGE is significantly and inversely correlated with components of the metabolic syndrome including body mass index, triglyceride, or an insulin resistance index. In a cohort of end-stage renal diseases (ESRD), cumulative incidence of cardiovascular death is significantly higher in subjects in the lowest tertile of plasma esRAGE, independent of the presence of diabetes. Moreover, adenoviral overexpression of esRAGE in mice significantly recovered vascular dysfunction in diabetes. Thus, we postulate that plasma esRAGE is a potential protective factor and a novel biomarker against atherosclerosis and metabolic syndrome.