First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushyu, Japan.
FEBS Lett. 2010 Jan 4;584(1):61-6. doi: 10.1016/j.febslet.2009.11.082.
Although increased vascular permeability is known to be a major characteristic of diabetic vasculopathy, the precise mechanisms and relevance of advanced glycation end products (AGE) to hyperpermeability of vessels remains unclear. Here, we studied changes in cytoskeletal configuration and the signaling mechanism induced by AGE in human endothelial cells. AGE-BSA stimulation induced Rho activation, intercellular gap formation, prominent actin stress fiber and cell contraction without changing VE-cadherin, and subsequently transendothelial diffusion of FITC-labeled dextran. These processes induced by AGE-BSA were inhibited by either Rho-kinase inhibitor Y27632 or anti-RAGE antibody. We also showed that RhoA and RAGE spontaneously formed a complex. These findings suggest that activation of RAGE/Rho is involved in AGE-BSA-induced hyperpermeability through gap formation and actin reorganization in diabetes.
尽管血管通透性增加是糖尿病血管病变的主要特征，但晚期糖基化终产物 (AGE) 对血管高通透性的确切机制和相关性仍不清楚。在这里，我们研究了 AGE 在人内皮细胞中诱导的细胞骨架构象变化和信号转导机制。AGE-BSA 刺激诱导 Rho 激活、细胞间间隙形成、明显的肌动蛋白应力纤维和细胞收缩，而不改变 VE-钙粘蛋白，随后 FITC 标记的葡聚糖穿过血管内皮扩散。AGE-BSA 诱导的这些过程被 Rho 激酶抑制剂 Y27632 或抗 RAGE 抗体抑制。我们还表明，RhoA 和 RAGE 自发形成复合物。这些发现表明，RAGE/Rho 的激活通过糖尿病中间隙形成和肌动蛋白重排参与 AGE-BSA 诱导的通透性增加。
