Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions

• Published in: International journal of molecular sciences Vol. 23; no. 9; p. 4528
• Main Authors: Guindolet, Damien, Woodward, Ashley M, Gabison, Eric E, Argüeso, Pablo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.04.2022; MDPI
• Subjects: Apoptosis; Caspase-3; Cell culture; Cell death; Cell viability; Chemical compounds; Cornea; corneal epithelium; DNA fragmentation; dry eye; Dry Eye Syndromes - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Enzymes; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Experiments; Eye diseases; Gene expression; Gene silencing; Homeostasis; Humans; hyperosmotic stress; Inflammation; Interleukin 5; Morphology; Osmotic pressure; Pathogenesis; Pharmacology; Protein folding; Proteins; Sjogren's syndrome; Taurochenodeoxycholic Acid - pharmacology; Tauroursodeoxycholic acid; Transcription activation; Unfolded Protein Response; unfolded protein response; hyperosmotic stress; tauroursodeoxycholic acid; dry eye; corneal epithelium; endoplasmic reticulum stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23094528

Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor were markedly upregulated in patients with Sjögren's dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of and , two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease.