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

Autor: T. Franklin, M.A. Behzadian, Nagla Ghaley, Ruth B. Caldwell, Jinling Yang, Azza B. El-Remessy, Michael W. Brands
Rok vydání: 2017
Předmět:
Male
Vascular Endothelial Growth Factor A
0106 biological sciences
Cell Membrane Permeability
VEGF receptors
lcsh:Medicine
01 natural sciences
Antioxidants
Glycogen Synthase Kinase 3
Mice
chemistry.chemical_compound
0302 clinical medicine
Superoxides
Blood-Retinal Barrier
lcsh:Science
Cells
Cultured
beta Catenin
Multidisciplinary
biology
Reverse Transcriptase Polymerase Chain Reaction
Superoxide
medicine.anatomical_structure
Signal Transduction
medicine.medical_specialty
Blotting
Western
Blood–retinal barrier
Diabetes Mellitus
Experimental
Receptors
Urokinase Plasminogen Activator
Capillary Permeability
Cyclic N-Oxides
03 medical and health sciences
Diabetes mellitus
Internal medicine
medicine
Animals
Superoxide Dismutase
lcsh:R
Correction
Endothelial Cells
Retinal Vessels
medicine.disease
Rats
Mice
Inbred C57BL
Urokinase receptor
Glucose
Endocrinology
chemistry
030221 ophthalmology & optometry
biology.protein
lcsh:Q
Cattle
Spin Labels
010606 plant biology & botany
Zdroj: PLoS ONE
PLoS ONE, Vol 12, Iss 10, p e0186749 (2017)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0186749
Popis: 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.
Databáze: OpenAIRE
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