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Aims: Age-related macular degeneration (AMD), a major cause of legal blindness in the elderly, is associated with genetic and environmental risk factors, such as cigarette smoking. Recent evidence shows that cigarette smoke (CS) that contains high levels of potent oxidants preferably targets retinal pigment epithelium (RPE) leading to oxidative damage and apoptosis; however, the mechanisms are poorly understood. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in CS-related RPE apoptosis. Results: ER stress and proapoptotic gene C/EBP homologous protein (CHOP) were induced in the RPE/choroid complex from mice exposed to CS for 2 weeks and in human RPE cells treated with hydroquinone, a potent oxidant found at high concentrations in CS. Suppressing ER stress or inhibiting CHOP activation by pharmacological chaperones or genetic approaches attenuated hydroquinone-induced RPE cell apoptosis. In contrast to enhanced CHOP activation, protein level of active X-box binding protein 1 (XBP1), a major regulator of the adaptive UPR, was reduced in hydroquinone-treated cells. Conditional knockout of XBP1 gene in the RPE resulted in caspase-12 activation, increased CHOP expression, and decreased antiapoptotic gene Bcl-2. Furthermore, XBP1-deficient RPE cells are more sensitive to oxidative damage induced by hydroquinone or NaIO3, a CS-unrelated chemical oxidant. Conversely, overexpressing XBP1 protected RPE cells and attenuated oxidative stress-induced RPE apoptosis. Innovation and Conclusion: These findings provide strong evidence suggesting an important role of ER stress and the UPR in CS-related oxidative injury of RPE cells. Thus, the modulation of the UPR signaling may provide a promising target for the treatment of AMD. Antioxid. Redox Signal. 20, 2091–2106.

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Faculty of Technology ePrints Service  


Chen, C. -  Cano, M. -  Wang, J. J. -  Li, J. -  Huang, C. -  Yu, Q. -  Herbert, T. P. -  Handa, J. T. -  Zhang, S. X. - 

Id.: 70192893

Versión: 1.0

Estado: Final

Palabras claveB200 Pharmacology, Toxicology and Pharmacy - 

Tipo de recurso: Article  -  PeerReviewed  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

Requerimientos técnicos:  Browser: Any - 

Relación: [References] http://eprints.lincoln.ac.uk/28216/
[References] 10.1089/ars.2013.5240

Fecha de contribución: 08-nov-2017


* Chen, C. and Cano, M. and Wang, J. J. and Li, J. and Huang, C. and Yu, Q. and Herbert, T. P. and Handa, J. T. and Zhang, S. X. (2014) Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxidants and Redox Signaling, 20 (14). pp. 2091-2106. ISSN 1523-0864

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