Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Shao-Jun Chen, Jia-Fang Yang, Fan-Ping Kong, Ji-Long Ren, Ke Hao, Min Li, Yuan Yuan, Xin-Can Chen, Ri-Sheng Yu, Jun-Fa Li, Gareth Leng, Xue-Qun Chen*, Ji-Zeng Du

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 Ca2+, and PKC epsilon; 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 showthat 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.

Original languageEnglish
Pages (from-to)13199-13204
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume111
Issue number36
Early online date21 Aug 2014
DOIs
Publication statusPublished - 9 Sep 2014

Keywords

  • water permeability
  • high altitude
  • acute mountain sickness
  • ACUTE MOUNTAIN-SICKNESS
  • MESSENGER-RNA EXPRESSION
  • PROTEIN-KINASE-C
  • HIGH-ALTITUDE
  • BRAIN EDEMA
  • RAT-BRAIN
  • HORMONE-RECEPTORS
  • HYPOBARIC HYPOXIA
  • ARTERY OCCLUSION
  • ISCHEMIC-STROKE

Cite this