title: Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema.
abstract: Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca(2+), and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1(+) and AQP4(+), we show that transfected CRFR1(+) contributes to edema via transfected AQP4(+). In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Shao-Jun
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Jia-Fang
authors.initials: JF
authors.lastname: Yang
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Fan-Ping
authors.initials: FP
authors.lastname: Kong
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Ren
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Medical Imaging, 117th Hospital of the People's Liberation Army, Hangzhou 310013, China;
authors.forename: Xin-Can
authors.initials: XC
authors.lastname: Chen
authors.affiliation: Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China;
authors.forename: Ri-Sheng
authors.initials: RS
authors.lastname: Yu
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; and.
authors.forename: Jun-Fa
authors.initials: JF
authors.lastname: Li
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Leng
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; dujz@zju.edu.cn chewyg@zju.edu.cn.
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; dujz@zju.edu.cn chewyg@zju.edu.cn.
authors.forename: Ji-Zeng
authors.initials: JZ
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019332:Endothelin-1 / Q000378:metabolism; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D000099052:CRF Receptor, Type 1
chemical_list: D051401:Aquaporin 4; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: acute mountain sickness; high altitude; water permeability