Diabetes-induced Superoxide Anion and Breakdown of the Blood-retinal Barrier: Role of the VEGF/uPAR Pathway

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Aug 17

PMID 23951261

Citations 18

Authors

Azza B El-Remessy

Telina Franklin

Nagla Ghaley

Jinling Yang

Michael W Brands

Ruth B Caldwell

Mohamed Ali Behzadian

Affiliations

Soon will be listed here.

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.

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