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TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury

Transient receptor potential canonical 6 (TRPC6) channel is an important non-selective cation channel with a variety of physiological roles in the central nervous system. Evidence has shown that TRPC6 is involved in the process of experimental stroke; however, the underlying mechanisms remain unclea...

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Autores principales: Liu, Lu, Chen, Manli, Lin, Kun, Xiang, Xuwu, Yang, Jing, Zheng, Yueying, Xiong, Xiaoxing, Zhu, Shengmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884618/
https://www.ncbi.nlm.nih.gov/pubmed/33604333
http://dx.doi.org/10.3389/fcell.2020.594283
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author Liu, Lu
Chen, Manli
Lin, Kun
Xiang, Xuwu
Yang, Jing
Zheng, Yueying
Xiong, Xiaoxing
Zhu, Shengmei
author_facet Liu, Lu
Chen, Manli
Lin, Kun
Xiang, Xuwu
Yang, Jing
Zheng, Yueying
Xiong, Xiaoxing
Zhu, Shengmei
author_sort Liu, Lu
collection PubMed
description Transient receptor potential canonical 6 (TRPC6) channel is an important non-selective cation channel with a variety of physiological roles in the central nervous system. Evidence has shown that TRPC6 is involved in the process of experimental stroke; however, the underlying mechanisms remain unclear. In the present study, the role of astrocytic TRPC6 was investigated in an oxygen–glucose deprivation cell model and middle cerebral artery occlusion (MCAO) mouse model of stroke. HYP9 (a selective TRPC6 agonist) and SKF96365 (SKF; a TRPC antagonist) were used to clarify the exact functions of TRPC6 in astrocytes after ischemic stroke. TRPC6 was significantly downregulated during ischemia/reperfusion (IR) injury in cultured astrocytes and in cortices of MCAO mice. Application of HYP9 in vivo alleviated the brain infarct lesion, astrocytes population, apoptosis, and interleukin-6 (IL-6) and IL-1β release in mouse cortices after ischemia. HYP9 dose-dependently inhibited the downregulation of TRPC6 and reduced astrocytic apoptosis, cytotoxicity and inflammatory responses in IR insult, whereas SKF aggravated the damage in vitro. In addition, modulation of TRPC6 channel diminished IR-induced Ca(2+) entry in astrocytes. Furthermore, decreased Ca(2+) entry due to TRPC6 contributed to reducing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) nuclear translocation and phosphorylation. Overexpression of astrocytic TRPC6 also attenuated apoptosis, cytotoxicity, inflammatory responses, and NF-κB phosphorylation in modeled ischemia in astrocytes. The results of the present study indicate that the TRPC6 channel can act as a potential target to reduce both inflammatory responses and apoptosis in astrocytes during IR injury, subsequently attenuating ischemic brain damage. In addition, we provide a novel view of stroke therapy by targeting the astrocytic TRPC6 channel.
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spelling pubmed-78846182021-02-17 TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury Liu, Lu Chen, Manli Lin, Kun Xiang, Xuwu Yang, Jing Zheng, Yueying Xiong, Xiaoxing Zhu, Shengmei Front Cell Dev Biol Cell and Developmental Biology Transient receptor potential canonical 6 (TRPC6) channel is an important non-selective cation channel with a variety of physiological roles in the central nervous system. Evidence has shown that TRPC6 is involved in the process of experimental stroke; however, the underlying mechanisms remain unclear. In the present study, the role of astrocytic TRPC6 was investigated in an oxygen–glucose deprivation cell model and middle cerebral artery occlusion (MCAO) mouse model of stroke. HYP9 (a selective TRPC6 agonist) and SKF96365 (SKF; a TRPC antagonist) were used to clarify the exact functions of TRPC6 in astrocytes after ischemic stroke. TRPC6 was significantly downregulated during ischemia/reperfusion (IR) injury in cultured astrocytes and in cortices of MCAO mice. Application of HYP9 in vivo alleviated the brain infarct lesion, astrocytes population, apoptosis, and interleukin-6 (IL-6) and IL-1β release in mouse cortices after ischemia. HYP9 dose-dependently inhibited the downregulation of TRPC6 and reduced astrocytic apoptosis, cytotoxicity and inflammatory responses in IR insult, whereas SKF aggravated the damage in vitro. In addition, modulation of TRPC6 channel diminished IR-induced Ca(2+) entry in astrocytes. Furthermore, decreased Ca(2+) entry due to TRPC6 contributed to reducing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) nuclear translocation and phosphorylation. Overexpression of astrocytic TRPC6 also attenuated apoptosis, cytotoxicity, inflammatory responses, and NF-κB phosphorylation in modeled ischemia in astrocytes. The results of the present study indicate that the TRPC6 channel can act as a potential target to reduce both inflammatory responses and apoptosis in astrocytes during IR injury, subsequently attenuating ischemic brain damage. In addition, we provide a novel view of stroke therapy by targeting the astrocytic TRPC6 channel. Frontiers Media S.A. 2021-02-02 /pmc/articles/PMC7884618/ /pubmed/33604333 http://dx.doi.org/10.3389/fcell.2020.594283 Text en Copyright © 2021 Liu, Chen, Lin, Xiang, Yang, Zheng, Xiong and Zhu. http://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
Liu, Lu
Chen, Manli
Lin, Kun
Xiang, Xuwu
Yang, Jing
Zheng, Yueying
Xiong, Xiaoxing
Zhu, Shengmei
TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title_full TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title_fullStr TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title_full_unstemmed TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title_short TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
title_sort trpc6 attenuates cortical astrocytic apoptosis and inflammation in cerebral ischemic/reperfusion injury
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884618/
https://www.ncbi.nlm.nih.gov/pubmed/33604333
http://dx.doi.org/10.3389/fcell.2020.594283
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