Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor
Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor
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DOI：
10.1016/s0002-9440(10)64332-5
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发表时间：
2003-06-01
影响因子：
6
通讯作者：
Caldwell, RB
中科院分区：
文献类型：
--
作者：
El-Remessy, AB;Behzadian, MA;Caldwell, RB
这些实验的目的是确定活性氧（ROS）在血视网膜屏障（BRB）破坏中的具体作用，BRB是糖尿病早期血管功能障碍的特征。根据我们的数据显示，高葡萄糖增加了视网膜内皮细胞中一氧化氮、超氧化物和硝基酪氨酸的形成，我们假设ROS的过量形成导致糖尿病中BRB的分解。由于已知ROS可以诱导众所周知的内皮细胞有丝分裂原和通透性因子血管内皮生长因子（VEGF）的表达增加，我们还研究了它们对VEGF及其下游靶点尿激酶纤溶酶原激活物受体（uPAR）表达的影响。2周后，白蛋白渗漏分析证实了BRB的明显破坏。这种通透性缺陷与一氧化氮、脂质过氧化物和过氧亚硝酸盐生物标志物硝基酪氨酸形成的显著增加以及VEGF和uPAR表达的增加有关。用一氧化氮合酶抑制剂（n -omega-硝基- l -精氨酸甲酯，50 mg/kg/天）或过氧亚硝酸盐清除剂（尿酸，160 mg/kg/天）治疗可以阻断BRB的分解，阻止脂质过氧化物和酪氨酸硝化形成的增加，以及VEGF和uPAR表达的增加。综上所述，这些数据表明，早期糖尿病导致BRB分解的机制涉及活性氮促进VEGF和uPAR表达的作用。（美国病理学杂志2003,162:1995-2004）
The purpose of these experiments was to determine the specific role of reactive oxygen species (ROS) in the blood-retinal barrier (BRB) breakdown that characterizes the early stages of vascular dysfunction in diabetes. Based on our data showing that high glucose increases nitric oxide, superoxide, and nitrotyrosine formation in retinal endothelial cells, we hypothesized that excess formation of ROS causes BRB breakdown in diabetes. Because ROS are known to induce increases in expression of the well-known endothelial mitogen and permeability factor vascular endothelial growth factor (VEGF) we also examined their influence on the expression of VEGF and its downstream target urokinase plasminogen activator receptor (uPAR). After 2 weeks of streptozotocin-induced diabetes, analysis of albumin leakage confirmed a prominent breakdown of the BRB. This permeability defect was correlated with significant increases in the formation of nitric oxide, lipid peroxides, and the peroxynitrite biomarker nitrotyrosine as weft as with increases in the expression of VEGF and uPAR. Treatment with a nitric oxide synthase inhibitor (N-omega-nitro-L-arginine methyl ester, 50 mg/kg/day) or peroxynitrite scavenger (uric acid, 160 mg/kg/day) blocked the breakdown in the BRB and prevented the increases in formation of lipid peroxides and tyrosine nitration as well as the increases in expression of VEGF and uPAR. Taken together, these data indicate that early diabetes causes breakdown of the BRB by a mechanism involving the action of reactive nitrogen species in promoting expression of VEGF and uPAR. (Am J Pathol 2003, 162:1995-2004)