GRP78 translocation to the cell surface and O-GlcNAcylation of VE-Cadherin contribute to ER stress-mediated endothelial permeability

Raji Lenin, Peter G. Nagy, Kumar Abhiram Jha, Raja Shekhar Gangaraju

Research output: Contribution to journalArticle

Abstract

Increased O-GlcNAcylation, a well-known post-translational modification of proteins causally linked to various detrimental cellular functions in pathological conditions including diabetic retinopathy (DR). Previously we have shown that endothelial activation induced by inflammation and hyperglycemia results in the endoplasmic reticulum (ER) stress-mediated intercellular junction alterations accompanied by visual deficits in a tie2-TNF-α transgenic mouse model. In this study, we tested the hypothesis that increased ER stress via O-GlcNAcylation of VE-Cadherin likely contribute to endothelial permeability. We show that ER stress leads to GRP78 translocation to the plasma membrane, increased O-GlcNAcylation of proteins, particularly VE-Cadherin resulting in a defective complex partnering leading to the loss of retinal endothelial barrier integrity and increased transendothelial migration of monocytes. We further show an association of GRP78 with the VE-Cadherin under these conditions. Interestingly, cells exposed to ER stress inhibitor, tauroursodeoxycholic acid partially mitigated all these effects. Our findings suggest an essential role for ER stress and O-GlcNAcylation in altering the endothelial barrier function and reveal a potential therapeutic target in the treatment of DR.

Original languageEnglish (US)
Article number10783
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Endoplasmic Reticulum Stress
Permeability
Diabetic Retinopathy
Transendothelial and Transepithelial Migration
Intercellular Junctions
Post Translational Protein Processing
Hyperglycemia
Transgenic Mice
Monocytes
Cell Membrane
cadherin 5
Inflammation
Proteins

All Science Journal Classification (ASJC) codes

  • General

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GRP78 translocation to the cell surface and O-GlcNAcylation of VE-Cadherin contribute to ER stress-mediated endothelial permeability. / Lenin, Raji; Nagy, Peter G.; Jha, Kumar Abhiram; Gangaraju, Raja Shekhar.

In: Scientific reports, Vol. 9, No. 1, 10783, 01.12.2019.

Research output: Contribution to journalArticle

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