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

• Published in: The American journal of pathology Vol. 162; no. 6; pp. 1995 - 2004
• Main Authors: El-Remessy, Azza B., Behzadian, M. Ali, Abou-Mohamed, Gamal, Franklin, Telina, Caldwell, Robert W., Caldwell, Ruth B.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.06.2003; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Blood-Retinal Barrier - drug effects; Blood-Retinal Barrier - physiology; Body Weight - drug effects; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelial Growth Factors - genetics; Enzyme Inhibitors - pharmacology; Gene Expression; Intercellular Signaling Peptides and Proteins - genetics; Lipid Peroxidation; Lymphokines - genetics; Medical sciences; NG-Nitroarginine Methyl Ester - pharmacology; Nitrates - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitrites - metabolism; Oxidative Stress - physiology; Peroxynitrous Acid - antagonists & inhibitors; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species - metabolism; Receptors, Cell Surface - genetics; Receptors, Urokinase Plasminogen Activator; Regular; Retina - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Uric Acid - pharmacology; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Endocrinopathy; Tyrosine; Nitration; u-Plasminogen activator; Biochemical analysis; Blood retinal barrier; Retinopathy; Serine endopeptidases; Rat; Enzyme; Pathogenesis; Diabetes mellitus; Cytokine; Rodentia; Peptidases; Eye disease; Vertebrata; Experimental disease; Mammalia; Vascular endothelium growth factor; Animal; Hydrolases; Hemodynamics; Molecular biology
• ISSN: 0002-9440; 1525-2191
• 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 -ω-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.