Frontiers in Cellular Neuroscience (Apr 2017)
Aquaporin 4-Mediated Glutamate-Induced Astrocyte Swelling Is Partially Mediated through Metabotropic Glutamate Receptor 5 Activation
- Fang Yuan,
- Fang Yuan,
- Fang Yuan,
- Fang Yuan,
- Fang Yuan,
- Zhongfang Shi,
- Zhongfang Shi,
- Zhongfang Shi,
- Zhongfang Shi,
- Zhongfang Shi,
- Wei Zhang,
- Wei Zhang,
- Wei Zhang,
- Wei Zhang,
- Wei Zhang,
- Yang Lu,
- Yang Lu,
- Yang Lu,
- Yang Lu,
- Yang Lu,
- Yi Lu,
- Yi Lu,
- Yi Lu,
- Yi Lu,
- Yi Lu,
- Lixin Xu,
- Lixin Xu,
- Lixin Xu,
- Lixin Xu,
- Lixin Xu,
- Qing Fang,
- Qing Fang,
- Qing Fang,
- Qing Fang,
- Qing Fang,
- Min Wu,
- Min Wu,
- Min Wu,
- Min Wu,
- Min Wu,
- Mei Jia,
- Mei Jia,
- Mei Jia,
- Mei Jia,
- Mei Jia,
- Yujiao Wang,
- Yujiao Wang,
- Yujiao Wang,
- Yujiao Wang,
- Yujiao Wang,
- Liping Dong,
- Liping Dong,
- Liping Dong,
- Liping Dong,
- Liping Dong,
- Xu Yan,
- Xu Yan,
- Xu Yan,
- Xu Yan,
- Xu Yan,
- Shaohua Yang,
- Shaohua Yang,
- Shaohua Yang,
- Shaohua Yang,
- Shaohua Yang,
- Shaohua Yang
Affiliations
- Fang Yuan
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Fang Yuan
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Fang Yuan
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Fang Yuan
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Fang Yuan
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Zhongfang Shi
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Zhongfang Shi
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Zhongfang Shi
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Zhongfang Shi
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Zhongfang Shi
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Wei Zhang
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Wei Zhang
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Wei Zhang
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Wei Zhang
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Wei Zhang
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Yang Lu
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Yang Lu
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Yang Lu
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Yang Lu
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Yang Lu
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Yi Lu
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Yi Lu
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Yi Lu
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Yi Lu
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Yi Lu
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Lixin Xu
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Lixin Xu
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Lixin Xu
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Lixin Xu
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Lixin Xu
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Qing Fang
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Qing Fang
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Qing Fang
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Qing Fang
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Qing Fang
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Min Wu
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Min Wu
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Min Wu
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Min Wu
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Min Wu
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Mei Jia
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Mei Jia
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Mei Jia
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Mei Jia
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Mei Jia
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Yujiao Wang
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Yujiao Wang
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Yujiao Wang
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Yujiao Wang
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Yujiao Wang
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Liping Dong
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Liping Dong
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Liping Dong
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Liping Dong
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Liping Dong
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Xu Yan
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Xu Yan
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Xu Yan
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Xu Yan
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Xu Yan
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Shaohua Yang
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
- Shaohua Yang
- China National Clinical Research Center for Neurological DiseasesBeijing, China
- Shaohua Yang
- Beijing Key Laboratory of Central Nervous System InjuryBeijing, China
- Shaohua Yang
- Center of Stroke, Beijing Institute for Brain DisordersBeijing, China
- Shaohua Yang
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular DiseaseBeijing, China
- Shaohua Yang
- Department of Pharmacology and Neuroscience, University of North Texas Health Science CenterFort Worth, TX, USA
- DOI
- https://doi.org/10.3389/fncel.2017.00116
- Journal volume & issue
-
Vol. 11
Abstract
Astrocytes are one of the most abundant cell types in the mammalian central nervous system (CNS), and astrocyte swelling is the primary event associated with brain edema. Glutamate, the principal excitatory amino acid neurotransmitter in the CNS, is released at high levels after brain injury including cerebral ischemia. This leads to astrocyte swelling, which we previously demonstrated is related to metabotropic glutamate receptor (mGluR) activation. Aquaporin 4 (AQP4), the predominant water channel in the brain, is expressed in astrocyte endfeet and plays an important role in brain edema following ischemia. Studies recently showed that mGluR5 is also expressed on astrocytes. Therefore, it is worth investigating whether AQP4 mediates the glutamate-induced swelling of astrocytes via mGluR5. In the present study, we found that 1 mM glutamate induced astrocyte swelling, quantified by the cell perimeter, but it had no effect on astrocyte viability measured by the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Quantitative reverse transcription polymerase chain reaction analyses revealed that AQP4, among AQP1, 4, 5, 9 and 11, was the main molecular expressed in cultured astrocytes. Glutamate-induced cell swelling was accompanied by a concentration-dependent change in AQP4 expression. Furthermore, RNAi technology revealed that AQP4 gene silencing inhibited glutamate-induced astrocyte swelling. Moreover, we found that mGluR5 expression was greatest among the mGluRs in cultured astrocytes and was co-expressed with AQP4. Activation of mGluR5 in cultured astrocytes using (S)-3,5-dihydroxyphenylglycine (DHPG), an mGluR5 agonist, mimicked the effect of glutamate. This effect was abolished by co-incubation with the mGluR5 antagonist fenobam but was not influenced by DL-threo-β-benzyloxyaspartic acid (DL-TBOA), a glutamate transporter inhibitor. Finally, experiments in a rat model of transient middle cerebral artery occlusion (tMCAO) revealed that co-expression of mGluR5 and AQP4 was increased in astrocyte endfeet around capillaries in the penumbra, and this was accompanied by brain edema. Collectively, these results suggest that glutamate induces cell swelling and alters AQP4 expression in astrocytes via mGluR5 activation, which may provide a novel approach for the treatment of edema following brain injury.
Keywords