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J. Biol. Chem., Vol. 280, Issue 14, 13906-13912, April 8, 2005
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Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis*
From the Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521
The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitis-induced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 ± 1 versus 25 ± 5 cm H2O) and brain water accumulation (2 ± 1 versus 9 ± 1 µl) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a 
5-fold higher water permeability (Pf) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured Pf and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.
Received for publication, December 3, 2004 , and in revised form, January 31, 2005.
* This work was supported by National Institutes of Health Grants DK35124, EY13574, HL59198, EB00415 and HL73856, and a Research Development Program grant from the Cystic Fibrosis Foundation (to A. S. V.), and by a Wellcome Trust Clinician Scientist Fellowship (to M. C. P. sponsored by Sanjeev Krishna). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: 1246 Health Sciences East Tower, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521. Tel.: 415-476-8530; Fax: 415-665-3847; E-mail: verkman{at}itsa.ucsf.edu.
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