Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling.
Aquaporin-4 (AQP4) is a water transport protein expressed in glial cell plasma membranes, including glial cell foot processes lining the blood-brain barrier. AQP4 deletion in mice reduces cytotoxic brain edema produced by different pathologies. To determine whether AQP4 is rate-limiting for brain water accumulation and whether altered AQP4 expression, as occurs in various pathologies, could have functional importance, we generated mice that overexpressed AQP4 in brain glial cells by a transgenic approach using the glial fibrillary acid protein promoter. Overexpression of AQP4 protein in brain by approximately 2.3-fold did not affect mouse survival, appearance, or behavior, nor did it affect brain anatomy or intracranial pressure (ICP). However, following acute water intoxication produced by intraperitoneal water injection, AQP4-overexpressing mice had an accelerated progression of cytotoxic brain swelling, with ICP elevation of 20 +/- 2 mmHg at 10 min, often producing brain herniation and death. In contrast, ICP elevation was 14 +/- 2 mmHg at 10 min in control mice and 9.8 +/- 2 mmHg in AQP4 knock-out mice. The deduced increase in brain water content correlated linearly with brain AQP4 protein expression. We conclude that AQP4 expression is rate-limiting for brain water accumulation, and thus, that altered AQP4 expression can be functionally significant.
Yang
Baoxue
B
Departments of Medicine and Physiology, University of California-San Francisco, 1246 Health Sciences East Tower, San Francisco, CA 94143-0521, USA.
Zador
Zsolt
Z
Verkman
A S
AS
D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D019586:Intracranial Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014869:Water Intoxication / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014882:Water-Electrolyte Balance / Q000235:genetics
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein