Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice
Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice
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DOI：
10.1161/01.atv.21.6.905
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发表时间：
2001-06-01
影响因子：
8.7
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
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作者：
Kislinger, T;Tanji, N;Schmidt, AM
晚期糖基化终产物(AGEs)及其细胞表面受体RAGE参与了糖尿病并发症的发病机制。在这里，我们研究了RAGE及其致炎配体的表达(S100/钙颗粒蛋白)在糖尿病组织中介导细胞激活的炎症事件中的作用。6周龄时，用链脲佐菌素造成载脂蛋白E缺失小鼠糖尿病模型。与非糖尿病大鼠的主动脉和肾脏相比，糖尿病大鼠的主动脉和肾脏RAGE、RAGE和血管炎症的两个关键标志血管细胞黏附分子(VCAM)-1和组织因子表达增加。给糖尿病小鼠服用可溶性RAGE(受体的胞外区或载体)6周，可抑制主动脉中VCAM-1和组织因子的水平，同时减少RAGE和愤怒的表达。糖尿病大鼠肾脏表现为肾小球内表达愤怒的炎症细胞增多，转化生长因子-β、纤维连接蛋白和α(1)(IV)胶原基因表达增强。在接受可溶性RAGE治疗的小鼠中，浸润性炎症细胞的数量和这些肾小球细胞因子和细胞外基质成分的mRNA水平减少。这些数据表明，在糖尿病组织中，RAGE起始细胞的激活是通过诱导促炎介质来进行的。
Advanced glycation end products (AGEs) and their cell surface receptor, RAGE, have been implicated in the pathogenesis of diabetic complications. Here, we studied the role of RAGE and expression of its proinflammatory ligands, EN-RAGEs (S100/calgranulins), in inflammatory events mediating cellular activation in diabetic tissue. Apolipoprotein E-null mice were rendered diabetic with streptozotocin at 6 weeks of age. Compared with nondiabetic aortas and kidneys, diabetic aortas and kidneys displayed increased expression of RAGE, EN-RAGEs, and 2 key markers of vascular inflammation, vascular cell adhesion molecule (VCAM)-1 and tissue factor. Administration of soluble RAGE, the extracellular domain of the receptor, or vehicle to diabetic mice for 6 weeks suppressed levels of VCAM-1 and tissue factor in the aorta, in parallel with decreased expression of RAGE and EN-RAGEs. Diabetic kidney demonstrated increased numbers of EN-RAGE-expressing inflammatory cells infiltrating the glomerulus and enhanced mRNA for transforming growth factor-beta, fibronectin, and alpha (1) (IV) collagen. In mice treated with soluble RAGE, the numbers of infiltrating inflammatory cells and mRNA levels for these glomerular cytokines and components of extracellular matrix were decreased. These data suggest that activation of RAGE primes cells targeted for perturbation in diabetic tissues by the induction of proinflammatory mediators.