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A Behzadian, AB El-Remessy, GI Liou, T Franklin, RB Caldwell; High Glucose Induces Urokinase Receptor (uPAR) Expression in Vascular Endothelial Cells: Evidence for Nitric Oxide Synthase and VEGF/flk-1 Involvement . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1281.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To study the mechanism of glucose-induced vascular hyperpermeability in diabetic retinopathy. Our previous findings indicate that a sustained VEGF-induced vascular hyper-permeability is associated with uPAR expression and uPA activities in bovine retinal endothelial (BRE) cells (Behzadian et al., ARVO 2001). We also have clear evidence that oxidative stress and formation of peroxynitrate play key roles in developing hyperglycemia-related vascular permeability in the streptozotocin-diabetic rat (El-Remessy et al., ARVO 2002). We hypothesize that increased peroxinitate formation by high glucose induces endothelial permeability by VEGF-mediated activation of extracellular proteases involving the uPA/ uPAR system. Methods: Bovine retinal endothelial (BRE) cells grown in serum free high glucose (25 mM) medium for five days, were treated as designated. Total RNA was extracted and analyzed for VEGF and uPAR gene expression by real time RT-PCR in a Light Cycler apparatus (Roche). Results: High glucose up-regulated uPAR gene expression in BRE cells. uPAR is known to focus plasmin and metalloproteinase activation on the cell surface, destabilizing cell-cell and cell-matrix attachments. Addition of superoxide dismutase (SOD), the SOD mimetic agent Tempol or the NOS inhibitor L-NAME abrogated glucose induced uPAR expression indicating that the uPAR upregulation involves superoxide, NO and probably peroxinitate (OONO -) formation. VEGF expression was increased by high glucose. An inhibitor of flk-1 activation (VEGFR tyrosine kinase inhibitor) blocked glucose effects on uPAR. Conclusion: Pathologic upregulation of VEGF in the eye has been well documented. Our data indicates that hyperglycemia induced blood/retinal barrier breakdown involves oxidative stress-induced and VEGF mediated uPA/uPAR activation in capillary endothelial cells.
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