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Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to...

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Autores principales: Semba, K, Namekata, K, Guo, X, Harada, C, Harada, T, Mitamura, Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123089/
https://www.ncbi.nlm.nih.gov/pubmed/25032856
http://dx.doi.org/10.1038/cddis.2014.296
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author Semba, K
Namekata, K
Guo, X
Harada, C
Harada, T
Mitamura, Y
author_facet Semba, K
Namekata, K
Guo, X
Harada, C
Harada, T
Mitamura, Y
author_sort Semba, K
collection PubMed
description Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Müller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Müller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin–angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP.
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spelling pubmed-41230892014-08-15 Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma Semba, K Namekata, K Guo, X Harada, C Harada, T Mitamura, Y Cell Death Dis Original Article Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Müller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Müller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin–angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP. Nature Publishing Group 2014-07 2014-07-17 /pmc/articles/PMC4123089/ /pubmed/25032856 http://dx.doi.org/10.1038/cddis.2014.296 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Semba, K
Namekata, K
Guo, X
Harada, C
Harada, T
Mitamura, Y
Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title_full Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title_fullStr Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title_full_unstemmed Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title_short Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
title_sort renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123089/
https://www.ncbi.nlm.nih.gov/pubmed/25032856
http://dx.doi.org/10.1038/cddis.2014.296
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