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

Azza B. El-Remessy, Telina Franklin, Nagla Ghaley, Jinling Yang, Michael W. Brands, Ruth B. Caldwell, Mohamed Ali Behzadian

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere71868
JournalPloS one
Volume8
Issue number8
DOIs
StatePublished - Aug 7 2013

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Blood-Retinal Barrier
Retinaldehyde
Urokinase Plasminogen Activator Receptors
u-plasminogen activator
vascular endothelial growth factors
Medical problems
Superoxides
superoxide anion
Vascular Endothelial Growth Factor A
diabetes
Blood
Endothelial cells
receptors
endothelial cells
blood
Endothelial Cells
Glucose
glucose
Catenins
Permeability

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier : Role of the VEGF/uPAR Pathway. / El-Remessy, Azza B.; Franklin, Telina; Ghaley, Nagla; Yang, Jinling; Brands, Michael W.; Caldwell, Ruth B.; Behzadian, Mohamed Ali.

In: PloS one, Vol. 8, No. 8, e71868, 07.08.2013.

Research output: Contribution to journalArticle

El-Remessy, Azza B. ; Franklin, Telina ; Ghaley, Nagla ; Yang, Jinling ; Brands, Michael W. ; Caldwell, Ruth B. ; Behzadian, Mohamed Ali. / Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier : Role of the VEGF/uPAR Pathway. In: PloS one. 2013 ; Vol. 8, No. 8.
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