Tauroursodeoxycholic Acid Alleviates Endoplasmic Reticulum Stress-Mediated Visual Deficits in Diabetic tie2-TNF Transgenic Mice via TGR5 Signaling.

Abstract

Purpose: This study evaluated if tauroursodeoxycholic acid (TUDCA) alleviates pro-inflammatory and endoplasmic reticulum (ER) stress-mediated visual deficits in diabetic tie2-TNF transgenic mice via Takeda G protein-coupled receptor 5 (TGR5) receptor signaling. Methods: Adult tie2-TNF transgenic or age-matched C57BL/6J (wildtype, WT) mice were made diabetic and treated subcutaneously with TUDCA. After 4 weeks, visual function, vascular permeability, immunohistology, and molecular analyses were assessed. Human retinal endothelial cells (HRECs) silenced for TGR5, followed by TNF and high glucose (HG) stress-mediated endothelial permeability, and transendothelial migration of activated leukocytes were assessed with TUDCA in vitro. Results: Compared with WT mice, tie2-TNF mice showed a decreased visual function correlated with a decrease in protein kinase C α (PKCα) in rod bipolar cells, and increased vascular permeability was further exacerbated in diabetic-tie2-TNF mice. Conversely, TUDCA alleviated these changes in diabetic mice. An increase in inflammation and ER stress in retina coincided with an increase in TGR5 expression in diabetic tie2-TNF mice that decreased with TUDCA. In vitro, HRECs exposed to TNF+HG demonstrated >2-fold increase in TGR5 expression, a 3-fold increase in leukocyte transmigration with a concomitant increase in permeability. Although TUDCA reversed these effects, HRECs silenced for TGR5 and challenged with TUDCA or TGR5 agonist failed to reverse the TNF+HG induced effects. Conclusions: Our data suggest that TUDCA will serve as an excellent therapeutic agent for diabetic complications addressing both vascular and neurodegenerative changes in the retina. Perturbation of the TGR5 receptor in the retina might play a role in linking retinal ER stress to neurovascular dysfunction in diabetic retinopathy.