Aquaporin-4 Expression in Cultured Astrocytes after Fluid Percussion Injury

作者：Rao Kakulavarapu V Rama; Reddy Pichili V B; Curtis Kevin M; Norenberg Michael D^*

来源：Journal of Neurotrauma, 2011, 28(3): 371-381.

DOI：10.1089/neu.2010.1705

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

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-kappa B), 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-kappa B 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-kappa B, and NKCC are involved in its upregulation.

• 出版日期2011-3