THE BELGIAN OPHTHALMIC ASSOCIATIONS
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This abstract is assigned to session Plenary Session: Jules François Foundation
| Title | Closing tight junctions opens the door to new treatment options for diabetic retinopathy |
| Abstract Nr. | A1083 |
| Purpose | Diabetic retinopathy is a leading cause of blindness among working age adults in Western Society. Increased vascular permeability is a hallmark of this disease and is closely associated with loss of vision. Vaso-active cytokines such as vascular endothelial growth factor (VEGF) contribute to the increased vascular permeability in diabetic retinopathy. Our laboratory has investigated the mechanisms by which VEGF and diabetes regulates vascular endothelial barrier properties in the retina. Specifically, we hypothesized that VEGF alters tight junction proteins to regulate barrier properties. Western blot analysis revealed that both diabetes and VEGF induce a change in the phosphorylation state of the tight junction protein occludin. Occludin phosphorylation and barrier properties are regulated by protein kinase C activation, as demonstrated by both chemical inhibitors of the kinase and transfection of cells with dominant negative protein kinase C. Additionally, immunocytochemistry with confocal microscopy of cells in culture and whole retinas showed that both VEGF and diabetes cause the redistribution of occludin and other tight junction proteins away from the plasma membrane to the cell interior. The change in tight junction protein distribution closely correlated with increased paracellular permeability measured by in vitro and in vivo functional assays. Biochemical isolation of triton-insoluble buoyant fractions containing tight junction proteins and isolation of endosomes support the hypothesis that specific tight junction proteins redistribute to the cytoplasm through vesicle formation and migration through an endosomal pathway. Finally, diabetes and VEGF reduce occludin protein content overtime. In contrast, glucocorticoids stimulate the synthesis and assembly of tight junction proteins, reduce the phosphorylation state of occludin, and decrease the permeability of the vascular endothelial barrier. Therefore, regulation of tight junction function with glucocorticoids offers a means to reduce vascular permeability in diabetic retinopathy and other diseases that involve failure of the blood-retinal and blood-brain barriers. Future work on the mechanism of steroid action may provide more specific means of regulating barrier properties. |
Author 1
| Last name | Antonetti |
| Initials | D |
| Department | Department of Cellular and Molecular Physiology, Penn State College of Medicine |
| City | Hershey, USA |