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

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.

Critical role of endoplasmic reticulum stress in chronic endothelial activation−induced visual deficits in tie2‐tumor necrosis factor mice

“…As seen from our administration of TUDCA, which is under clinical trials for treatment of amyotrophic lateral sclerosis (NCT03127514; AMX0035 in Patients With Amyotrophic Lateral Sclerosis) and diabetes (NCT02218619; TUDCA in New‐Onset Type 1 Diabetes), it is plausible that ER stress inhibitors could be of therapeutic value in DR and other diabetic complications. In support of this, other ER stress inhibitors, 4‐phenylbutyrate and ursodeoxycholic acid have shown successful alleviation of ER stress‐induced pathology in retinal inflammation . Future studies, beyond the scope of this study will explore the administration of TUDCA in our diabetic tie2‐TNF mice to evaluate this supposition.…”

Protective effect of melatonin in the diabetic rat retina

“…Chung et al showed that ursodeoxycholic acid improved vascular integrity and decreased the fluorescein dye leakage during angiography in retina of STZ-induced diabetic mice. They found that ursodeoxycholic acid attenuated the DR via reducing oxidative stress [42]. Nakao et al [43] reported that MEL has ameliorative effects on angiotensin II-induced vascular endothelial damage through its antioxidant properties.…”

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

“…Additionally, induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were assessed in diabetic mice and human retinal pericytes exposed to AGEs recently, to elucidate their role in DR [30]. According to Chung and associates' research, under the application of AGEs, multiple ER stress markers, specifically phosphorylated eukaryotic translation initiation factor-2α (peIF-2α) and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were significantly upregulated, whereas this can be attenuated by ursodeoxycholic acid (UDCA), a known ameliorator of ER stress.…”

“…According to Chung and associates' research, under the application of AGEs, multiple ER stress markers, specifically phosphorylated eukaryotic translation initiation factor-2α (peIF-2α) and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were significantly upregulated, whereas this can be attenuated by ursodeoxycholic acid (UDCA), a known ameliorator of ER stress. Consequently, vascular integrity was protected and pericyte loss was reduced in the retina of STZ-induced diabetic mice [30]. UPR is supposed as a cellular mechanism activated to overcome ER stress and restore cellular homeostasis, however it may induce apoptotic death in cases of prolonged and severe ER stress [30,31].…”

“…Consequently, vascular integrity was protected and pericyte loss was reduced in the retina of STZ-induced diabetic mice [30]. UPR is supposed as a cellular mechanism activated to overcome ER stress and restore cellular homeostasis, however it may induce apoptotic death in cases of prolonged and severe ER stress [30,31]. Apart from UPR, autophagy is also regarded as a cytoprotective mechanism utilized by pericytes, until a critical stress threshold is exceeded [32].…”