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Download fileVascular Expression of Permeability-Resistant Occludin Mutant Preserves Visual Function in Diabetes
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posted on 2021-04-21, 16:21 authored by Andreia Goncalves, Alyssa Dreffs, Cheng-mao Lin, Sarah Sheskey, Natalie Hudson, Jason Keil, Matthew Campbell, David A. AntonettiDiabetic retinopathy is one of the leading causes of vision loss
and blindness. Extensive pre-clinical and clinical evidence exists for both
vascular and neuronal pathology. However, the relationship of these changes in
the neurovascular unit and impact on vision remains to be determined. Here, we
investigate the role of tight junction protein occludin phosphorylation at S490
in modulating barrier properties and its impact on visual function. Conditional
vascular expression of the phosphorylation resistant Ser490 to Ala (S490A) form
of occludin preserved tight junction organization and reduced VEGF-induced
permeability and edema formation after intra-ocular injection. In the retinas
of streptozotocin-induced diabetic mice, endothelial specific expression of the
S490A form of occludin completely prevented diabetes-induced permeability to
labeled dextran and inhibited leukostasis. Importantly, vascular-specific
expression of the occludin mutant completely blocked the diabetes-induced
decrease in visual acuity and contrast sensitivity. Together, these results
reveal that occludin acts to regulate barrier properties downstream of VEGF in
a phosphorylation dependent manner and that loss of inner blood-retinal barrier
(iBRB) integrity induced by diabetes contributes to vision loss.