Aquaporin-4 expression in cultured astrocytes after fluid percussion injury

Kakulavarapu V.Rama Rao, Pichili V.B. Reddy, Kevin M. Curtis, Michael D. Norenberg

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The development of cytotoxic brain edema resulting in increased intracranial pressure is a major cause of death occurring in the early phase of traumatic brain injury (TBI). Such edema predominantly develops as a consequence of astrocyte swelling. We recently documented that fluid percussion injury (FPI) to cultured astrocytes causes cell swelling. Since aquaporin-4 (AQP4) has been strongly implicated in the development of brain edema/astrocyte swelling in various neurological conditions, this study examined the effect of in vitro trauma on AQP4 protein expression in cultured astrocytes. Exposure of astrocytes to FPI resulted in a significant upregulation of AQP4 protein in the plasma membrane due to neosynthesis, as cycloheximide blocked the trauma-induced AQP4 upregulation. Silencing the aqp4 gene by siRNA resulted in a significant reduction in trauma-induced astrocyte swelling, indicating a critical role of AQP4 in this process. We recently documented that oxidative/nitrative stress (ONS), the mitochondrial permeability transition (mPT), and activation of mitogen-activated protein kinases (MAPKs), contribute to trauma-induced astrocyte swelling in culture. We now show that inhibition of these factors reduces the upregulation of AQP4 following trauma. Since TBI has been shown to activate nuclear factor-kappa B (NF-κB), as well as the Na +,K+,Cl- co-transporter (NKCC), both of which are implicated in brain edema/astrocyte swelling in other conditions, we also examined the effect of BAY 11-7082 and bumetanide, inhibitors of NF-κB and NKCC, respectively, and found that these agents also significantly inhibited the trauma-induced AQP4 upregulation. Our findings show that in vitro trauma upregulates AQP4, and that ONS, MAPKs, mPT, NF-κB, and NKCC are involved in its upregulation.

Original languageEnglish (US)
Pages (from-to)371-381
Number of pages11
JournalJournal of neurotrauma
Volume28
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • aquaporin-4
  • astrocyte swelling
  • brain edema
  • Na,K ,Cl co-transporter
  • oxidative/nitrative stress
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

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