Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo
Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo
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DOI：
10.2337/diabetes.48.10.2052
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发表时间：
1999-10-01
期刊：
影响因子：
7.7
通讯作者：
Vicaut, E
中科院分区：
文献类型：
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作者：
Bonnardel-Phu, E;Wautier, JL;Vicaut, E
晚期糖基化终末产物(AGEs)是糖尿病和衰老过程中在血管组织中积累的蛋白质的非酶糖基化加合物。这项工作的目的是研究AGEs在糖尿病引起的血管通透性改变中的作用和氧化机制。采用活体视频显微镜观察提睾肌白蛋白微血管渗漏情况。测定荧光大分子示踪剂(异硫氰酸荧光素-白蛋白)外渗1h，经计算机图像分析后，表示为归一化灰度级(任意单位)的变化。糖尿病大鼠的大分子示踪剂的外渗量比对照组大鼠高得多(外渗斜率随时间增加了100%，P<；10(-4))。静脉注射可溶性重组AGE受体(RR-RAGE)(0.5、2.5和5.15 mg/kg RR-RAGE，外渗斜率随时间分别下降19、30和40%)或静脉注射6 mg/kg抗RAGE抗体(斜率下降53%)，可显著抑制AGEs与其内皮受体的结合。全身注射普罗布考(抗氧化剂)也显著抑制实验性糖尿病大分子示踪剂外渗量的增加(斜率下降51%，P<；10(-4))。这些结果有力地表明，在实验性糖尿病中，循环AGEs和内皮RAGE的相互作用可能通过年龄依赖性增强的氧化应激来介导白蛋白微血管渗漏。
Advanced glycation end products (AGEs) are nonenzymatic glycosylated adducts of proteins that accumulate in vascular tissue during diabetes and aging. The aim of this work was to study the role of AGEs and of the oxidative mechanisms in diabetes-induced changes in vascular permeability. Intravital videomicroscopy was used to study albumin microvascular leakage in cremaster muscle. The extravasation of a fluorescent macromolecular tracer (fluorescein isothiocyanate-albumin) was measured for 1 h and, after computer-aided image analysis, was expressed as variations of normalized gray levels (arbitrary units). Extravasation of the macromolecular tracer was much higher in diabetic rats than in control rats (slope of extravasation versus time increased by >100%, P < 10(-4)). This increase was significantly inhibited when we blocked AGEs binding to their endothelial receptor by intravenous bolus of soluble recombinant receptor to AGEs (rR-RAGE) (slope of extravasation versus time decreased by 19, 30, and 40%, for 0.5, 2.5, and 5.15 mg/kg rR-RAGE, respectively) or by a 6 mg/kg intravenous bolus of antibody against RAGE (slope decreased by 53%). Systemic injection of probucol tan antioxidant) also significantly inhibited the increase in the extravasation of the macromolecular tracer occurring in experimental diabetes (slope decreased by 51%, P < 10(-4)). These results strongly suggest that in experimental diabetes the interaction of circulating AGEs and endothelial RAGE mediates albumin micro-vascular leakage, possibly via AGE-RAGE-dependent enhanced oxidant stress.