title: Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia.
abstract: The formation of brain edema, commonly occurring as a potentially lethal complication of acute hyponatremia, is delayed following knockout of the water channel aquaporin-4 (AQP4). Here we show by high-resolution immunogold analysis of the blood-brain-barrier that AQP4 is expressed in brain endothelial cells as well as in the perivascular membranes of astrocyte endfeet. A selective removal of perivascular AQP4 by alpha-syntrophin deletion delays the buildup of brain edema (assessed by Diffusion-weighted MRI) following water intoxication, despite the presence of a normal complement of endothelial AQP4. This indicates that the perivascular membrane domain, which is peripheral to the endothelial blood-brain barrier, may control the rate of osmotically driven water entry. This study is also the first to demonstrate that the time course of edema development differs among brain regions, probably reflecting differences in aquaporin-4 distribution. The resolution of the molecular basis and subcellular site of osmotically driven brain water uptake should help design new therapies for acute brain edema.
authors.affiliation: Centre for Molecular Biology and Neuroscience, and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Amiry-Moghaddam
authors.forename: Rong
authors.initials: R
authors.lastname: Xue
authors.forename: Finn-Mogens
authors.initials: FM
authors.lastname: Haug
authors.forename: John D
authors.initials: JD
authors.lastname: Neely
authors.forename: Anish
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Peter
authors.initials: P
authors.lastname: Agre
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Froehner
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
mesh_terms: D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000172:deficiency / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000502:physiology*; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D022081:Cell Surface Extensions / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006706:Homeostasis; D007010:Hyponatremia / Q000150:complications; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019579:Neocortex / Q000378:metabolism; D009928:Organ Specificity; D014867:Water / Q000378:metabolism
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C091825:syntrophin alpha1; D014867:Water