Ursodeoxycholic Acid Attenuates Endoplasmic Reticulum Stress-Related Retinal Pericyte Loss in Streptozotocin-Induced Diabetic Mice.

Yoo-Ri Chung,Young Hee Yoon,Jae-Young Koh,Jeong A Choi

doi:10.1155/2017/1763292

Abstract

Loss of pericytes, an early hallmark of diabetic retinopathy (DR), results in breakdown of the blood-retinal barrier. Endoplasmic reticulum (ER) stress may be involved in this process. The purpose of this study was to examine the effects of ursodeoxycholic acid (UDCA), a known ameliorator of ER stress, on pericyte loss in DR of streptozotocin- (STZ-) induced diabetic mice. To assess the extent of DR, the integrity of retinal vessels and density of retinal capillaries in STZ-induced diabetic mice were evaluated. Additionally, induction of ER stress and the unfolded protein response (UPR) were assessed in diabetic mice and human retinal pericytes exposed to advanced glycation end products (AGE) or modified low-density lipoprotein (mLDL). Fluorescein dye leakage during angiography and retinal capillary density were improved in UDCA-treated diabetic mice, compared to the nontreated diabetic group. Among the UPR markers, those involved in the protein kinase-like ER kinase (PERK) pathway were increased, while UDCA attenuated UPR in STZ-induced diabetic mice as well as AGE- or mLDL-exposed retinal pericytes in culture. Consequently, vascular integrity was improved and pericyte loss reduced in the retina of STZ-induced diabetic mice. Our findings suggest that UDCA might be effective in protecting against DR.

Highlights

Diabetic retinopathy (DR), a retinal microvascular disease, is one of the leading causes of severe vision loss among the working-age population [1, 2]
Using fluorescein angiography obtained with a retinal imaging system for living mice (Micron III), we examined the effect of ursodeoxycholic acid (UDCA) on vascular integrity in diabetic mice
Increased fluorescein leakage was observed at a late phase in retinas of STZ diabetic mice, compared with controls, which was significantly attenuated upon UDCA treatment (Figures 1(a) and 1(b))

Summary

Introduction

Diabetic retinopathy (DR), a retinal microvascular disease, is one of the leading causes of severe vision loss among the working-age population [1, 2]. Proliferative retinopathy and diabetic macular edema are major complications of DR and lead to severe visual impairment [3]. Strict control of blood glucose as well as early detection and treatment are often effective measures in preventing severe vision loss due to DR [3]. The pathogenesis of DR is extremely complex, involving multiple mechanisms. Pericytes are essential in the maintenance of vascular integrity/BRB, and their functional abnormalities and eventual loss may play a critical role in the breakdown of BRB in DR [1, 4, 8,9,10]. Loss of pericytes subsequently results in vascular abnormalities accompanied by upregulation of angiogenic

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