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Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression

Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical r...

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Autores principales: Xu, Bohan, Zhou, Linbin, Chen, Qishan, Zhang, Jianing, Huang, Lijuan, Wang, Shasha, Ye, Zhimin, Ren, Xiangrong, Cai, Yu, Jensen, Lasse Dahl, Chen, Weirong, Li, Xuri, Ju, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249873/
https://www.ncbi.nlm.nih.gov/pubmed/34222224
http://dx.doi.org/10.3389/fcell.2021.631413
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author Xu, Bohan
Zhou, Linbin
Chen, Qishan
Zhang, Jianing
Huang, Lijuan
Wang, Shasha
Ye, Zhimin
Ren, Xiangrong
Cai, Yu
Jensen, Lasse Dahl
Chen, Weirong
Li, Xuri
Ju, Rong
author_facet Xu, Bohan
Zhou, Linbin
Chen, Qishan
Zhang, Jianing
Huang, Lijuan
Wang, Shasha
Ye, Zhimin
Ren, Xiangrong
Cai, Yu
Jensen, Lasse Dahl
Chen, Weirong
Li, Xuri
Ju, Rong
author_sort Xu, Bohan
collection PubMed
description Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression.
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spelling pubmed-82498732021-07-03 Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression Xu, Bohan Zhou, Linbin Chen, Qishan Zhang, Jianing Huang, Lijuan Wang, Shasha Ye, Zhimin Ren, Xiangrong Cai, Yu Jensen, Lasse Dahl Chen, Weirong Li, Xuri Ju, Rong Front Cell Dev Biol Cell and Developmental Biology Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression. Frontiers Media S.A. 2021-06-18 /pmc/articles/PMC8249873/ /pubmed/34222224 http://dx.doi.org/10.3389/fcell.2021.631413 Text en Copyright © 2021 Xu, Zhou, Chen, Zhang, Huang, Wang, Ye, Ren, Cai, Jensen, Chen, Li and Ju. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Xu, Bohan
Zhou, Linbin
Chen, Qishan
Zhang, Jianing
Huang, Lijuan
Wang, Shasha
Ye, Zhimin
Ren, Xiangrong
Cai, Yu
Jensen, Lasse Dahl
Chen, Weirong
Li, Xuri
Ju, Rong
Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title_full Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title_fullStr Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title_full_unstemmed Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title_short Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
title_sort role of vegfr2 in mediating endoplasmic reticulum stress under glucose deprivation and determining cell death, oxidative stress, and inflammatory factor expression
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249873/
https://www.ncbi.nlm.nih.gov/pubmed/34222224
http://dx.doi.org/10.3389/fcell.2021.631413
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