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Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis
Glaucoma including primary open-angle glaucoma (POAG) results from elevations in intraocular pressure (IOP). An eye-localized renin-angiotensin system (RAS) has been implicated in IOP regulation, although its mechanism of action and contribution to glaucoma is poorly understood. Here, we detected si...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068978/ https://www.ncbi.nlm.nih.gov/pubmed/36999649 http://dx.doi.org/10.1177/09636897231162526 |
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author | Li, Haijun Cui, Huiling Ren, Jing Wang, Di Zhao, Rumeng Zhu, Shichao Liu, Siqing Liu, Xiaohui Tian, Shuai Zhang, Yuanyuan Zhao, Panpan Li, Peng Thorne, Rick F. Duan, Shichao |
author_facet | Li, Haijun Cui, Huiling Ren, Jing Wang, Di Zhao, Rumeng Zhu, Shichao Liu, Siqing Liu, Xiaohui Tian, Shuai Zhang, Yuanyuan Zhao, Panpan Li, Peng Thorne, Rick F. Duan, Shichao |
author_sort | Li, Haijun |
collection | PubMed |
description | Glaucoma including primary open-angle glaucoma (POAG) results from elevations in intraocular pressure (IOP). An eye-localized renin-angiotensin system (RAS) has been implicated in IOP regulation, although its mechanism of action and contribution to glaucoma is poorly understood. Here, we detected significant increases in the levels of angiotensin II (ANGII) in aqueous humor samples from POAG patients. Moreover, we determined that the concentrations of ANGII were positively correlated with IOP, suggesting a role for elevated ANGII levels in eye pathogenesis. Functional investigations demonstrated that ANGII induces the expression of fibrosis-related genes of transformed and primary human trabecular meshwork cells (HTMCs) through the transcriptional upregulation of key fibrotic genes. Parallel experiments using a murine periocular conjunctival fornix injection model confirmed that ANGII induces the expression of fibrosis-related genes in trabecular meshwork (TM) cells in vivo along with increasing IOP. ANGII was revealed to function through increasing the levels of reactive oxygen species (ROS) via selectively upregulating NOX4, with NOX4 knockdown or inhibition with GLX351322 alleviating fibrotic changes induced by ANGII. We further show that ANGII activates Smad3, with both GLX351322 and an inhibitor of Smad3 (SIS3) decreasing the phosphorylation of Smad3 and dampening the ANGII-induced increases in fibrotic proteins. Moreover, NOX4 and Smad3 inhibitors also partially rescued the elevated IOP levels induced by ANGII. Our collective results therefore highlight ANGII as a biomarker and treatment target in POAG together with establishing a causal relationship between ANGII and up-regulation of the expression of fibrosis-related genes of TM cells via a NOX4/ROS axis in cooperation with TGFβ/Smad3 signaling. |
format | Online Article Text |
id | pubmed-10068978 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-100689782023-04-04 Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis Li, Haijun Cui, Huiling Ren, Jing Wang, Di Zhao, Rumeng Zhu, Shichao Liu, Siqing Liu, Xiaohui Tian, Shuai Zhang, Yuanyuan Zhao, Panpan Li, Peng Thorne, Rick F. Duan, Shichao Cell Transplant Original Article Glaucoma including primary open-angle glaucoma (POAG) results from elevations in intraocular pressure (IOP). An eye-localized renin-angiotensin system (RAS) has been implicated in IOP regulation, although its mechanism of action and contribution to glaucoma is poorly understood. Here, we detected significant increases in the levels of angiotensin II (ANGII) in aqueous humor samples from POAG patients. Moreover, we determined that the concentrations of ANGII were positively correlated with IOP, suggesting a role for elevated ANGII levels in eye pathogenesis. Functional investigations demonstrated that ANGII induces the expression of fibrosis-related genes of transformed and primary human trabecular meshwork cells (HTMCs) through the transcriptional upregulation of key fibrotic genes. Parallel experiments using a murine periocular conjunctival fornix injection model confirmed that ANGII induces the expression of fibrosis-related genes in trabecular meshwork (TM) cells in vivo along with increasing IOP. ANGII was revealed to function through increasing the levels of reactive oxygen species (ROS) via selectively upregulating NOX4, with NOX4 knockdown or inhibition with GLX351322 alleviating fibrotic changes induced by ANGII. We further show that ANGII activates Smad3, with both GLX351322 and an inhibitor of Smad3 (SIS3) decreasing the phosphorylation of Smad3 and dampening the ANGII-induced increases in fibrotic proteins. Moreover, NOX4 and Smad3 inhibitors also partially rescued the elevated IOP levels induced by ANGII. Our collective results therefore highlight ANGII as a biomarker and treatment target in POAG together with establishing a causal relationship between ANGII and up-regulation of the expression of fibrosis-related genes of TM cells via a NOX4/ROS axis in cooperation with TGFβ/Smad3 signaling. SAGE Publications 2023-03-31 /pmc/articles/PMC10068978/ /pubmed/36999649 http://dx.doi.org/10.1177/09636897231162526 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Article Li, Haijun Cui, Huiling Ren, Jing Wang, Di Zhao, Rumeng Zhu, Shichao Liu, Siqing Liu, Xiaohui Tian, Shuai Zhang, Yuanyuan Zhao, Panpan Li, Peng Thorne, Rick F. Duan, Shichao Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title | Elevated Angiotensin-II Levels Contribute to the Pathogenesis of
Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in
Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title_full | Elevated Angiotensin-II Levels Contribute to the Pathogenesis of
Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in
Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title_fullStr | Elevated Angiotensin-II Levels Contribute to the Pathogenesis of
Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in
Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title_full_unstemmed | Elevated Angiotensin-II Levels Contribute to the Pathogenesis of
Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in
Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title_short | Elevated Angiotensin-II Levels Contribute to the Pathogenesis of
Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in
Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis |
title_sort | elevated angiotensin-ii levels contribute to the pathogenesis of
open-angle glaucoma via inducing the expression of fibrosis-related genes in
trabecular meshwork cells through a ros/nox4/smad3 axis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068978/ https://www.ncbi.nlm.nih.gov/pubmed/36999649 http://dx.doi.org/10.1177/09636897231162526 |
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