Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke

Abstract

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Effect of water intoxication on survival in AQP4+/+ and AQP4−/− mice.
Figure 2: Localization and quantitation of cerebral edema following water intoxication.
Figure 3: Neurological outcome following MCA occlusion AQP4+/+ and AQP4−/− mice.
Figure 4: Histological analysis of AQP4+/+ and AQP4−/− mice after ischemia.

Similar content being viewed by others

References

  1. Klatzo, I. Neuropathological aspects of brain edema. Acta Neurochir.Suppl. 60, 3–6 (1994).

    CAS  Google Scholar 

  2. Fishman, R. Brain edema. N. Eng. J. Med. 293, 706–711 (1975).

    Article  CAS  Google Scholar 

  3. Weed, L.H. & McKibben, P.S. Experimental alteration of brain bulk. Am. J. Physiol. 48, 531–558 (1919).

    Article  Google Scholar 

  4. Verkman, A.S. et al. Water transport across mammalian cell membranes. Am. J. Physiol. 48, C12–C30 (1996).

    Article  Google Scholar 

  5. King, L.S. & Agre, P. Pathophysiology of the aquaporin water channels. Ann. Rev. Physiol. 58, 619–648 (1996).

    Article  CAS  Google Scholar 

  6. Nielsen, S., Smith, B.L., Christensen, E.I. & Agre, P. Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc. Natl. Acad. Sci. USA 90, 7275–7279 (1993).

    Article  CAS  Google Scholar 

  7. Hasegawa, H., Zhang, R., Dohrman, A. & Verkman, A.S. Tissue-specific expression of mRNA encoding the rat kidney water channel CHIP28k by in situ hybridization. Am. J. Physiol. 264, C237–C245 (1993).

    Article  CAS  Google Scholar 

  8. Frigeri, A., Gropper, M., Turck, C.W. & Verkman, A.S. Immunolocalization of the mercurial-insensitive water channel and glycerol intrinsic protein in epithelial cell plasma membranes. Proc. Natl. Acad. Sci. USA 92, 4328–4331 (1995).

    Article  CAS  Google Scholar 

  9. Nielsen, S. et al. Specialized membrane domains for water transport in glial cells: high- resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neuro. 17, 171–180 (1997).

    Article  CAS  Google Scholar 

  10. Ma, T. et al. Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J. Clin. Invest. 100, 957–962 (1997).

    Article  CAS  Google Scholar 

  11. Trachtman, H. Cell volume regulation: a review of cerebral adaptive mechanisms and implications for clinical treatment of osmolal disturbances. Ped. Nephrol. 1992, 104–112 (1992).

    Article  Google Scholar 

  12. Hossman, K.A. Experimental models for the investigation of brain ischemia. Cardiovasc. Res. 39, 106–120 (1998).

    Article  Google Scholar 

  13. Kondo, T. et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17, 4180–4189 (1997).

    Article  CAS  Google Scholar 

  14. Gullans, S.R. & Verbalis, J.G. Control of brain volume during hypoosmolar and hypoosmolar conditions. Annu. Rev, Med. 44, 289–301 (1993).

    Article  CAS  Google Scholar 

  15. Wasterlain, C.G. & Torack, R.M. Cerebral edema in water intoxication. II. An ultrastructural study. Arch. Neurol. 19, 79–87 (1968).

    Article  CAS  Google Scholar 

  16. Marmarou, A., Poll, W., Shulman, K. & Bhagavan, H. A simple gravimetric technique for measurement of cerebral edema. J. Neurosurg. 49, 530–537 (1978).

    Article  CAS  Google Scholar 

  17. Nelson, S.R., Mantz, M.L. & Maxwell, J.A. Use of specific gravity in the measurement of cerebral edema. J. Appl. Physiol. 30, 268–271 (1971).

    Article  CAS  Google Scholar 

  18. Hasegawa, H., Ma, T., Skach, W., Matthay, M. & Verkman, A.S. Molecular cloning of a mercurial-insensitive water channel expressed in selected water transporting tissues. J. Biol. Chem. 269, 5497–5500 (1994).

    CAS  Google Scholar 

  19. Jung, J.S. et al. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc. Natl. Acad. Sci. USA 91, 13052–13056 (1994).

    Article  CAS  Google Scholar 

  20. Kimelberg, H. K. Current concepts of brain edema. Review of laboratory investigations. J. Neuro. 83, 1051–1059 (1995).

    CAS  Google Scholar 

  21. Bullock, R., Maxwell, W.L. & Graham, D.I. Glial swelling following cerebral contusion: an ultrstructural study. J. Neurol. Neurosurg. Psychiatry 54, 427–434 (1991).

    Article  CAS  Google Scholar 

  22. Wasterlain, C.G. & Posner, J.B. Cerebral edema in water intoxication. I. Clinical and chemical observations. Arch. Neurol. 19, 71–78 (1968).

    Article  CAS  Google Scholar 

  23. Landis, D.M. & Reese, T.S. Arrays of particles in freeze-fractures of astrocytic membranes. J. Cell. Biol. 60, 316–320 (1974).

    Article  CAS  Google Scholar 

  24. Frigeri, A. et al. Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. J. Cell. Sci. 108, 2993–3002 (1995).

    CAS  Google Scholar 

  25. Yang, B., Brown, D. & Verkman, A.S. The mercurial-insensitive water channel (AQP-4) form orthogonal arrays in stably transfected CHO cells. J. Biol. Chem. 271, 4577–4580 (1996).

    Article  CAS  Google Scholar 

  26. Verbavatz, J.M., Ma, T., Gobin, R. & Verkman, A.S. Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4. J. Cell Sci. 110, 2855–2860 (1997).

    CAS  Google Scholar 

  27. Rash, J.E., Yasumura, T., Hudson, C.S., Agre, P. & Nielsen, S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membrane in rat brain and spinal cord. Proc. Natl. Acad. Sci. USA 95, 11981–11986 (1998).

    Article  CAS  Google Scholar 

  28. Nagelhus, E.A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by acoenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).

    Article  CAS  Google Scholar 

  29. Suzuki, M. et al. Disintegration of orthogonal arrays in perivascular astrocytic foot processes as an early event in acute global ischemia. Brain Res. 300, 141–145 (1984).

    Article  CAS  Google Scholar 

  30. Hatton, J.D. & Ellisman, M.H. Orthogonal arrays are redistributed in the membranes of astroglia from alumina-induced epileptic foci. Epilepsia 25, 145–151 (1984).

    Article  CAS  Google Scholar 

  31. Carrillo, P. et al. Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage. J. Trauma 45, 239–248; discussion 248–239 (1998).

    Article  CAS  Google Scholar 

  32. Fujimura, M. et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J. Neurosci. 19, 3414–3422 (1999).

    Article  CAS  Google Scholar 

  33. Yang, G. et al. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 25, 165–170 (1994).

    Article  Google Scholar 

  34. Swanson, R. A. et al. A semiautomated method for measuring brain infarct volume. J. Cereb. Blood Flow. Metab. 10, 290–293 (1990).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Fishman and A. Marmarou for advice and critical discussions about edema models and quantitation of brain tissue water. We also thank. L. Qian for breeding and genotyping of transgenic mice and electron microscopy technologists J. Beck and M. Yoshimura. This work was supported by grants from the National Institutes of Health and National Cystic Fibrosis Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Geoffrey T. Manley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Manley, G., Fujimura, M., Ma, T. et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6, 159–163 (2000). https://doi.org/10.1038/72256

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/72256

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing