Abstract
Diabetes-induced breakdown of the blood-retinal barrier (BRB) has been linked to hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and is likely mediated by an increase in oxidative stress. We have shown that VEGF increases permeability of retinal endothelial cells (REC) by inducing expression of urokinase plasminogen activator receptor (uPAR). The purpose of this study was to define the role of superoxide anion in VEGF/uPAR expression and BRB breakdown in diabetes. Studies were performed in streptozotocin diabetic rats and mice and high glucose (HG) treated REC. The superoxide dismutase (SOD) mimetic tempol blocked diabetes-induced permeability and uPAR expression in rats and the cell permeable SOD inhibited HG-induced expression of uPAR and VEGF in REC. Inhibiting VEGFR blocked HG-induced expression of VEGF and uPAR and GSK-3β phosphorylation in REC. HG caused β-catenin translocation from the plasma membrane into the cytosol and nucleus. Treatment with HG-conditioned media increased REC paracellular permeability that was blocked by anti-uPA or anti-uPAR antibodies. Moreover, deletion of uPAR blocked diabetes-induced BRB breakdown and activation of MMP-9 in mice. Together, these data indicate that diabetes-induced oxidative stress triggers BRB breakdown by a mechanism involving uPAR expression through VEGF-induced activation of the GSK3β/β-catenin signaling pathway.
Highlights
Breakdown of the blood-retinal barrier (BRB) occurs early in diabetic retinopathy and leads to vascular leakage and retinal edema [1,2]
Based on our previous studies linking diabetes-induced BRB breakdown to activation of the uPA/urokinase plasminogen activator receptor (uPAR) pathway [4], we examined the effects of inhibiting superoxide anion on expression of uPAR
The main findings of this study are as follows: 1. Reducing superoxide anion blocked diabetes-induced vascular permeability in vivo and high glucose-induced expression of vascular endothelial growth factor (VEGF) and uPAR in vitro (Figures 1, 2, 3). 2
Summary
Breakdown of the blood-retinal barrier (BRB) occurs early in diabetic retinopathy and leads to vascular leakage and retinal edema [1,2]. Increases in vascular endothelial growth factor (VEGF) are evident in retinal tissue and ocular fluids of diabetic patients and animals and are likely mediated by an increase in oxidative stress [4,5,6,7,8,9]. Anti-VEGF therapies have shown promise in reducing vascular leakage and macular edema in diabetic patients. In light of the potential for adverse effects with repeated anti-VEGF injections and the beneficial actions of VEGF as a survival factor (reviewed in 13), there is great need for additional anti-permeability therapies. A more precise definition of the mechanisms involved in the diabetes-induced permeability increase is needed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
