期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：36
页码：13199-13204
DOI：10.1073/pnas.1404493111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHigh-altitude cerebral edema, a serious and often fatal condition, results from lowered oxygen supply. This study explores the mechanisms by which hypoxia induces cerebral edema. We show that hypoxia induced cerebral edema and neuronal apoptosis associated with increased expression of the neuropeptide corticotrophin releasing factor (CRF) and its type 1 receptor (CRFR1), the water channel aquaporin-4 (AQP4), and endothelin-1; these effects could be blocked by the CRFR1 antagonist. In cultured astrocytes, CRF, acting through CRFR1, triggers intracellular signaling and contributes to phosphorylation and expression of AQP4 to enhance water influx into cells. These data provide an understanding of the development of cerebral edema by high-altitude hypoxia and suggest that CRFR1 might be a target molecule for prevention of this disorder. 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 Ca2+, and PKC{varepsilon}; 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.
关键词：water permeability ; high altitude ; acute mountain sickness
