The Unfolded Protein Response and Diabetic Retinopathy

Abstract

Diabetic retinopathy, a common complication of diabetes, is the leading cause of blindness in adults. Diabetes chronically damages retinal blood vessels and neurons likely through multiple pathogenic pathways such as oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. To relieve ER stress, the cell activates an adaptive mechanism known as the unfolded protein response (UPR). The UPR coordinates the processes of protein synthesis, protein folding, and degradation to ensure proteostasis, which is vital for cell survival and activity. Emerging evidence suggests that diabetes can activate all three UPR branches in retinal cells, among which the PERK/ATF4 pathway is the most extensively studied in the development of diabetic retinopathy. X-box binding protein 1 (XBP1) is a major transcription factor in the core UPR pathway and also regulates a variety of genes involved in cellular metabolism, redox state, autophagy, inflammation, cell survival, and vascular function. The exact function and implication of XBP1 in the pathogenesis of diabetic retinopathy remain elusive. Focusing on this less studied pathway, we summarize recent progress in studies of the UPR pertaining to diabetic changes in retinal vasculature and neurons, highlighting the perspective of XBP1 as a potential therapeutic target in diabetic retinopathy.

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

“…genetic), duration of diabetes, species and strains of animals, and methods used to examine the UPR components. Nevertheless, these studies provide evidence of ER stress and activation of the UPR in DR (also reviewed in (Hu, Liu et al 2012, Jing, Wang et al 2012, Ma, Wang et al 2014)).…”

“…In the current review, we discuss the role of the UPR in regulation of retinal angiogenesis and interrelated processes, such as vasodegeneration, vascular remodeling, angiogenic progenitor function and vascular repair, highlighting the novel implication of ER-related signaling pathways in the retinal vascular system. For a recent review on the role of ER stress and the UPR in the context of the pathobiology of retinal degenerations, see Zhang et al (Zhang et al, 2014). …”

Diabetes and Age-Related Differences in Vascular Function of Renal Artery: Possible Involvement of Endoplasmic Reticulum Stress

“…13,16,17 Recently, several studies have demonstrated that dysfunction of the ER, or ER stress, is involved in the pathogenesis of diabetes and its complications and the aging process. 14,16,[18][19][20][21][22] Moreover, some reports have suggested the association between ER stress and the vascular function in pathophysiological states. Spitler et al 23 reported that ER stress was increased in the spontaneously hypertensive rat (SHR) aorta, and treatment with chemical chaperones, such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (PBA), ameliorated the increased EDCF-mediated contraction via suppression of the cytosolic phospholipase A 2 (cPLA 2 )/COX pathway.…”

Induction of Activating Transcription Factor 6 via Activation of ERK and ROS-P38 MAPK is Related to Methylglyoxal-Induced Cytotoxicity in Human Retinal Pigment Epithelial Cells

“…Also, the ER stress pathway activates many diabetic complications including DR, and well-known ER stress-related factors (CHOP, ATF4, and GRP78/BiP) are involved in the progression of DR [16][17][18][19][20]. This is a novel finding that the induction of ATF6 occurs in MGO-treated RPE.…”

“…Previous reports have shown that the ER stress pathway activates many diabetic complications including DR [17][18][19]. Also, various ER stress-related factors such as CHOP and ATF4 are involved in the progression of DR [16,20].…”