The endoplasmic reticulum (ER) is the primary intracellular organelle responsible for protein and lipid biosynthesis, protein folding and trafficking, calcium homeostasis, and several other vital processes in cell physiology. Disturbance in ER function results in ER stress and subsequent activation of the unfolded protein response (UPR). The UPR up-regulates ER chaperones, reduces protein translation, and promotes clearance of cytotoxic misfolded proteins to restore ER homeostasis. If this vital process fails, the cell will be signaled to enter apoptosis, resulting in cell death. Sustained ER stress also can trigger an inflammatory response and exacerbate oxidative stress, both of which contribute synergistically to tissue damage. Studies performed over the past decade have implicated ER stress in a broad range of human diseases, including neurodegenerative diseases, cancer, diabetes, and vascular disorders. Several of these diseases also entail retinal dysfunction and degeneration caused by injury to retinal neurons and/or to the blood vessels that supply retinal cells with nutrients, trophic and homeostatic factors, oxygen, and other essential molecules, as well as serving as a conduit for removal of waste products and potentially toxic substances from the retina. Collectively, such injuries represent the leading cause of blindness world-wide in all age groups. Herein, we summarize recent progress on the study of ER stress and UPR signaling in retinal biology and discuss the molecular mechanisms and the potential clinical applications of targeting ER stress as a new therapeutic approach to prevent and treat neuronal degeneration in the retina.

The endoplasmic reticulum (ER) is the primary cellular compartment where proteins are synthesized and modified before they can be transported to their destination. Dysfunction of the ER impairs protein homeostasis and leads to the accumulation of misfolded/unfolded proteins in the ER, or ER stress. While it has long been recognized that ER stress is a major cause of conformational disorders, such as Alzheimer's disease, Huntington's disease, certain types of cancer, and type 2 diabetes, recent evidence suggests that ER stress is also implicated in many chronic inflammatory diseases. These diseases include irritable bowel syndrome, atherosclerosis, diabetic complications, and many others. Diabetic retinopathy is a common microvascular complication of diabetes, characterized by chronic inflammation, progressive damage to retinal vascular and neuronal cells, vascular leakage, and abnormal blood vessel growth (neovascularization). In this review, we discuss the role and mechanisms of ER stress in retinal inflammation and vascular damage in diabetic retinopathy.

BACKGROUND AND OBJECTIVES: Acute severe neurologic involvement is the most threatening complication in children with hemolytic-uremic syndrome (HUS). Our primary study objectives were to describe the association between acute neurologic manifestations (ANMs) and in-hospital mortality among children with HUS. METHODS: Using the Pediatric Health Information System database, in this retrospective multicenter cohort study, we identified the first HUS-related inpatient visit among children ≤18 years (years 2004–2018). Frequency of selected ANMs and combinations of ANMs, as well as the rate of mortality, was calculated. Multivariate logistic regression was used to identify the association of ANMs and the risk of in-hospital mortality. RESULTS: Among 3915 patients included in the analysis, an ANM was noted in 10.4% (n = 409) patients. Encephalopathy was the most common ANM (n = 245). Mortality was significantly higher among patients with an ANM compared with patients without an ANM (13.9% vs 1.8%; P < .001). Individuals with any ANM had increased odds of mortality (odds ratio [OR]: 2.25; 95% confidence interval [CI]: 1.29–3.93; P = .004), with greater risk (OR: 2.60; 95% CI: 1.34–5.06; P = .005) among patients with ≥2 manifestations. Brain hemorrhage (OR: 3.09; 95% CI: 1.40–6.82; P = .005), brain infarction (OR: 2.64; 95% CI: 1.10–6.34; P = .03), anoxic brain injury (OR: 3.92; 95% CI: 1.49–10.31; P = .006), and brain edema (OR: 4.81; 95% CI: 1.82–12.71; P = .002) were independently associated with mortality. CONCLUSIONS: In this study, the largest systematic assessment of ANMs among children with HUS to date, we identify differences in in-hospital mortality based on the type of ANM, with increased risk observed for patients with multiple ANMs.

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