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Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes
Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress–induced activating transcription factor 4 (ATF4) in the regulation of Müller cell–derived in...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266398/ https://www.ncbi.nlm.nih.gov/pubmed/22228718 http://dx.doi.org/10.2337/db11-0315 |
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author | Zhong, Yimin Li, Jingming Chen, Yanming Wang, Joshua J. Ratan, Rajiv Zhang, Sarah X. |
author_facet | Zhong, Yimin Li, Jingming Chen, Yanming Wang, Joshua J. Ratan, Rajiv Zhang, Sarah X. |
author_sort | Zhong, Yimin |
collection | PubMed |
description | Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress–induced activating transcription factor 4 (ATF4) in the regulation of Müller cell–derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Müller cells in the retina. In cultured Müller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Müller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH(2)-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress–induced and hypoxia-inducible factor-1α activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Müller cell–derived inflammatory cytokine production in diabetes. |
format | Online Article Text |
id | pubmed-3266398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-32663982013-02-01 Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes Zhong, Yimin Li, Jingming Chen, Yanming Wang, Joshua J. Ratan, Rajiv Zhang, Sarah X. Diabetes Complications Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress–induced activating transcription factor 4 (ATF4) in the regulation of Müller cell–derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Müller cells in the retina. In cultured Müller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Müller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH(2)-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress–induced and hypoxia-inducible factor-1α activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Müller cell–derived inflammatory cytokine production in diabetes. American Diabetes Association 2012-02 2012-01-17 /pmc/articles/PMC3266398/ /pubmed/22228718 http://dx.doi.org/10.2337/db11-0315 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Complications Zhong, Yimin Li, Jingming Chen, Yanming Wang, Joshua J. Ratan, Rajiv Zhang, Sarah X. Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title | Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title_full | Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title_fullStr | Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title_full_unstemmed | Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title_short | Activation of Endoplasmic Reticulum Stress by Hyperglycemia Is Essential for Müller Cell–Derived Inflammatory Cytokine Production in Diabetes |
title_sort | activation of endoplasmic reticulum stress by hyperglycemia is essential for müller cell–derived inflammatory cytokine production in diabetes |
topic | Complications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266398/ https://www.ncbi.nlm.nih.gov/pubmed/22228718 http://dx.doi.org/10.2337/db11-0315 |
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