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Jacey Hongjie Ma, Jingming Li, Joshua Jianxin Wang, Sarah Xin Zhang; X-box Binding Protein 1 (XBP1) is a Crucial Regulator of Endothelial Tight Junction and Protects the Blood-retinal barrier in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2253.
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Breakdown of the blood-retinal barrier (BRB) is one of the most important features of diabetic retinopathy (DR) and is largely attributed to disruption of endothelial tight junction. The aim of our study is to decipher the role of X-box binding protein 1 (XBP1), a major transcription factor activated by ER stress, in regulation of endothelial tight junction and BRB function in normal and diabetic conditions.
Primary human retinal endothelial cells (HRECs), mouse retinal endothelial cells (MRECs) and mouse brain endothelial cells (MBECs) were used for in vitro study. Endothelial cell-specific XBP1 knockout (XBP1EC-/-) mice were generated and crossed with db/+ mice to produce a type 2 diabetic XBP1-KO mouse model (XBP1EC-/-/db/db). A separate group of XBP1EC-/- mice with controls received 5 consecutive intraperitoneal injections of streptozotocin to induce type 1 diabetes.
Treatment of HRECs with the ER stress inducer tunicamycin and thapsigargin resulted in decreased protein levels of ZO-1 and claudin-5, increased phosphorylation of occludin, disrupted tight junction and reduced trans-endothelial electrical resistance (TEER). These changes were exacerbated in cells pre-treated with pharmacological inhibitor of XBP1 splicing. XBP1EC-/- mice exhibit reduced ZO-1 and claudin 5 expressions, defective endothelial tight junction, and increased vascular permeability in the retina. Diabetes-induced BRB breakdown and permeability increase were worsened in XBP1EC-/-/db/db mice when compare to wild type. Similar results were observed in STZ-induced type 1 diabetes model. Furthermore, XBP1-deficient endothelial cells derived from XBP1EC-/- mice were more sensitive to VEGF- and TNF-α-initiated disruption of tight junction proteins.
Our findings provide the first evidence that XBP1 is important for maintaining endothelial barrier function, and that activation of XBP1 protects against ER stress-induced tight junction damage. Future studies will investigate whether overexpressing active XBP1 could restore BRB function in diabetic retinopathy and to identify potential pathways by which XBP1 regulates endothelial tight junction.
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