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Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration

The renin–angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the ‘classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in w...

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Autores principales: Valenzuela, Rita, Costa-Besada, Maria A, Iglesias-Gonzalez, Javier, Perez-Costas, Emma, Villar-Cheda, Begoña, Garrido-Gil, Pablo, Melendez-Ferro, Miguel, Soto-Otero, Ramon, Lanciego, Jose L, Henrion, Daniel, Franco, Rafael, Labandeira-Garcia, Jose L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133991/
https://www.ncbi.nlm.nih.gov/pubmed/27763643
http://dx.doi.org/10.1038/cddis.2016.327
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author Valenzuela, Rita
Costa-Besada, Maria A
Iglesias-Gonzalez, Javier
Perez-Costas, Emma
Villar-Cheda, Begoña
Garrido-Gil, Pablo
Melendez-Ferro, Miguel
Soto-Otero, Ramon
Lanciego, Jose L
Henrion, Daniel
Franco, Rafael
Labandeira-Garcia, Jose L
author_facet Valenzuela, Rita
Costa-Besada, Maria A
Iglesias-Gonzalez, Javier
Perez-Costas, Emma
Villar-Cheda, Begoña
Garrido-Gil, Pablo
Melendez-Ferro, Miguel
Soto-Otero, Ramon
Lanciego, Jose L
Henrion, Daniel
Franco, Rafael
Labandeira-Garcia, Jose L
author_sort Valenzuela, Rita
collection PubMed
description The renin–angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the ‘classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2). A combination of in vivo (rats, wild-type mice and knockout mice) and in vitro (primary mesencephalic cultures, dopaminergic neuron cell line cultures) experimental approaches (confocal microscopy, electron microscopy, laser capture microdissection, transfection of fluorescent-tagged receptors, treatments with fluorescent angiotensin, western blot, polymerase chain reaction, HPLC, mitochondrial respirometry and other functional assays) were used in the present study. We report the discovery of AT1 and AT2 receptors in brain mitochondria, particularly mitochondria of dopaminergic neurons. Activation of AT1 receptors in mitochondria regulates superoxide production, via Nox4, and increases respiration. Mitochondrial AT2 receptors are much more abundant and increase after treatment of cells with oxidative stress inducers, and produce, via nitric oxide, a decrease in mitochondrial respiration. Mitochondria from the nigral region of aged rats displayed altered expression of AT1 and AT2 receptors. AT2-mediated regulation of mitochondrial respiration represents an unrecognized primary line of defence against oxidative stress, which may be particularly important in neurons with increased levels of oxidative stress such as dopaminergic neurons. Altered expression of AT1 and AT2 receptors with aging may induce mitochondrial dysfunction, the main risk factor for neurodegeneration.
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spelling pubmed-51339912016-12-16 Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration Valenzuela, Rita Costa-Besada, Maria A Iglesias-Gonzalez, Javier Perez-Costas, Emma Villar-Cheda, Begoña Garrido-Gil, Pablo Melendez-Ferro, Miguel Soto-Otero, Ramon Lanciego, Jose L Henrion, Daniel Franco, Rafael Labandeira-Garcia, Jose L Cell Death Dis Original Article The renin–angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the ‘classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2). A combination of in vivo (rats, wild-type mice and knockout mice) and in vitro (primary mesencephalic cultures, dopaminergic neuron cell line cultures) experimental approaches (confocal microscopy, electron microscopy, laser capture microdissection, transfection of fluorescent-tagged receptors, treatments with fluorescent angiotensin, western blot, polymerase chain reaction, HPLC, mitochondrial respirometry and other functional assays) were used in the present study. We report the discovery of AT1 and AT2 receptors in brain mitochondria, particularly mitochondria of dopaminergic neurons. Activation of AT1 receptors in mitochondria regulates superoxide production, via Nox4, and increases respiration. Mitochondrial AT2 receptors are much more abundant and increase after treatment of cells with oxidative stress inducers, and produce, via nitric oxide, a decrease in mitochondrial respiration. Mitochondria from the nigral region of aged rats displayed altered expression of AT1 and AT2 receptors. AT2-mediated regulation of mitochondrial respiration represents an unrecognized primary line of defence against oxidative stress, which may be particularly important in neurons with increased levels of oxidative stress such as dopaminergic neurons. Altered expression of AT1 and AT2 receptors with aging may induce mitochondrial dysfunction, the main risk factor for neurodegeneration. Nature Publishing Group 2016-10 2016-10-20 /pmc/articles/PMC5133991/ /pubmed/27763643 http://dx.doi.org/10.1038/cddis.2016.327 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International 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/4.0/
spellingShingle Original Article
Valenzuela, Rita
Costa-Besada, Maria A
Iglesias-Gonzalez, Javier
Perez-Costas, Emma
Villar-Cheda, Begoña
Garrido-Gil, Pablo
Melendez-Ferro, Miguel
Soto-Otero, Ramon
Lanciego, Jose L
Henrion, Daniel
Franco, Rafael
Labandeira-Garcia, Jose L
Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title_full Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title_fullStr Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title_full_unstemmed Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title_short Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration
title_sort mitochondrial angiotensin receptors in dopaminergic neurons. role in cell protection and aging-related vulnerability to neurodegeneration
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133991/
https://www.ncbi.nlm.nih.gov/pubmed/27763643
http://dx.doi.org/10.1038/cddis.2016.327
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