El-Remessy Azza B, Behzadian M Ali, Abou-Mohamed Gamal, Franklin Telina, Caldwell Robert W, Caldwell Ruth B
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30909, USA.
Am J Pathol. 2003 Jun;162(6):1995-2004. doi: 10.1016/S0002-9440(10)64332-5.
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 well 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.
这些实验的目的是确定活性氧（ROS）在血视网膜屏障（BRB）破坏中所起的具体作用，BRB破坏是糖尿病血管功能障碍早期阶段的特征。基于我们的数据显示高糖会增加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，我们推测ROS的过量形成会导致糖尿病中BRB的破坏。由于已知ROS会诱导著名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型纤溶酶原激活剂受体（uPAR）表达的影响。在链脲佐菌素诱导的糖尿病2周后，白蛋白渗漏分析证实了BRB的显著破坏。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的形成显著增加以及VEGF和uPAR的表达增加相关。用一氧化氮合酶抑制剂（N-ω-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）治疗可阻断BRB的破坏，并防止脂质过氧化物形成和酪氨酸硝化增加以及VEGF和uPAR表达增加。综上所述，这些数据表明早期糖尿病通过一种涉及活性氮物质促进VEGF和uPAR表达的机制导致BRB的破坏。
