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Vascular Expression of Permeability-Resistant Occludin Mutant Preserves Visual Function in Diabetes

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posted on 21.04.2021, 16:21 by Andreia Goncalves, Alyssa Dreffs, Cheng-mao Lin, Sarah Sheskey, Natalie Hudson, Jason Keil, Matthew Campbell, David A. Antonetti
Diabetic 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.

Funding

This work was supported by NIH National Eye Institute R01 EY012021 (DAA), core NIH grants P30 EY007003 (Kellogg Eye Center Core Center for Vision Research) and DK020572 (Michigan Diabetes Research Center), post-doctoral fellowship T32EY013934-18 (AG) and the Roger W. Kittendorf Research professorship (DAA). The Campbell lab at Trinity College Dublin was supported by The Irish Research Council and by a Science Foundation Ireland (SFI) Centres grant supported in part by a research grant from SFI under grant number 16/RC/3948 and co-funded under the European Regional Development fund by FutureNeuro industry partners.

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