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Downregulation of Aquaporin-4 Protects Brain Against Hypoxia Ischemia via Anti-inflammatory Mechanism

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Abstract

Aquaporin-4 (AQP4), a water-channel protein, controls water fluxes into and out of the brain parenchyma. The role of AQP4 in brain edema formation and resolution remains controversial. This study therefore determined the roles of AQP4 in brain edema and explored the underlying molecular mechanism. We established hypoxia-ischemia (HI) neonatal rat model in vivo and HI cell model in vitro, which were administrated with lentiviral or shRNA vector, respectively. We found that the neurologic deficit and motor dysfunction could be induced by HI with more serious brain damage after longer HI time, and swollen cells with enlarged surrounding space were observed after HI induction. The quantity of water in the brain tissues was significantly increased in the HI rats when compared with the control group. However, the downregulation AQP4 by lentiviral or shRNA vector reversed the brain edema and neurologic deficit induced by HI. The underlying mechanism of beneficial effects of AQP4 downregulation may be due to interactive regulation of AQP4 and inflammatory cytokines including IL-1β, IL-6, IL-10, and TNFα. Our data demonstrate that the silence of AQP4 results in a significant decrease in the expression of IL-1β, IL-10, and TNFα, but had no direct effect on IL-6 expression. AQP4 could indirectly regulate the expression of IL-6 via IL-1β, IL-10, and TNFα. In summary, these findings provide a novel mechanism to explain the role of AQP4 in HI pathogenesis and are instrumental for the development of treatment for HI-induced brain edema.

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Acknowledgments

This study is supported by a grant from the National High-tech R&D Program (863 Program No. 2015AA020310), the National Natural Science Foundation of China (Nos. 81501071, 815300045, 81373166), Shenzhen Development and Reform Commission and Shenzhen Municipal Science and Technology Innovation Council (20140405201035).

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Authors and Affiliations

  1. Shenzhen Children’s Hospital, Shenzhen, Guangdong, 710038, China

    Sujuan Liu, Juan Mao & Xuemei Fu

  2. Department of Anatomy and Histology, School of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China

    Sujuan Liu

  3. Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, China

    Tinghua Wang

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Correspondence to Xuemei Fu.

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Liu, S., Mao, J., Wang, T. et al. Downregulation of Aquaporin-4 Protects Brain Against Hypoxia Ischemia via Anti-inflammatory Mechanism. Mol Neurobiol 54, 6426–6435 (2017). https://doi.org/10.1007/s12035-016-0185-8

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  • DOI: https://doi.org/10.1007/s12035-016-0185-8

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