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Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure

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Abstract

Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation, and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, nonselective cation (NCCa-ATP) channel. We therefore examined its potential role in the astrocyte swelling/brain edema associated with ALF. Cultured astrocytes treated with 5 mM ammonia showed a threefold increase in the sulfonylurea receptor type 1 (SUR1) protein expression, a marker of NCCa-ATP channel activity. Blocking SUR1 with glibenclamide significantly reduced the ammonia-induced cell swelling in cultured astrocytes. Additionally, overexpression of SUR1 in ammonia-treated cultured astrocytes was significantly reduced by cotreatment of cells with BAY 11–7082, an inhibitor of NF-κB, indicating the involvement of an NF-κB-mediated SUR1 upregulation in the mechanism of ammonia-induced astrocyte swelling. Brain SUR1 mRNA level was also found to be increased in the thioacetamide (TAA) rat model of ALF. Additionally, we found a significant increase in SUR1 protein expression in rat brain cortical astrocytes in TAA-treated rats. Treatment with glibenclamide significantly reduced the brain edema in this model of ALF. These findings strongly suggest the involvement of NCCa-ATP channel in the astrocyte swelling/brain edema in ALF and that targeting this channel may represent a useful approach for the treatment of the brain edema associated with ALF.

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Acknowledgments

This work was supported by a Merit Review from the Department of Veterans Affairs and by the National Institutes of Health grant DK063311. We thank Alina Fernandez-Revuelta for the preparation of cell cultures.

Conflict of Interest

Arumugam Jayakumar declares no conflict of interest. He does not have a financial relationship with any organization.

Vanessa Valdes declares no conflict of interest. She does not have a financial relationship with any organization.

Xiao Ying Tong declares no conflict of interest. She does not have a financial relationship with any organization.

Nagarajarao Shamaladevi declares no conflict of interest. She does not have a financial relationship with any organization.

Will Gonzalez declares no conflict of interest. He does not have a financial relationship with any organization.

Michael Norenberg declares no conflict of interest. He does not have a financial relationship with any organization.

Human subjects were not involved in this study.

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Authors and Affiliations

  1. Department of Pathology, University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL, 33101, USA

    A. R. Jayakumar, V. Valdes, W. Gonzalez & M. D. Norenberg

  2. Veterans Affairs Medical Center, Miami, FL, USA

    A. R. Jayakumar, X. Y. Tong & M. D. Norenberg

  3. Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

    N. Shamaladevi

  4. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    M. D. Norenberg

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  1. A. R. Jayakumar
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  2. V. Valdes
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  3. X. Y. Tong
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  4. N. Shamaladevi
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  5. W. Gonzalez
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  6. M. D. Norenberg
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Correspondence to M. D. Norenberg.

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Jayakumar, A.R., Valdes, V., Tong, X.Y. et al. Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure. Transl. Stroke Res. 5, 28–37 (2014). https://doi.org/10.1007/s12975-014-0328-z

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  • DOI: https://doi.org/10.1007/s12975-014-0328-z

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