Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice.
Cerebral water accumulation was studied during induction of brain edema in dystrophin-null transgenic mice (mdx-betageo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 (aquaporin-4) in astroglial end-feet surrounding capillaries (blood-brain barrier) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58% +/- 2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55% +/- 3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the blood-brain barrier and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema.
Vajda
Zsolt
Z
Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus, Denmark.
Pedersen
Michael
M
Füchtbauer
Ernst-Martin
EM
Wertz
Karin
K
Stødkilde-Jørgensen
Hans
H
Sulyok
Endre
E
Dóczi
Tamás
T
Neely
John D
JD
Agre
Peter
P
Frøkiaer
Jørgen
J
Nielsen
Søren
S
D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000096:biosynthesis*; D001127:Arginine Vasopressin / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics* / Q000502:physiology*; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000378:metabolism; D013687:Telencephalon / Q000378:metabolism; D013997:Time Factors; D014867:Water / Q000378:metabolism
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D016189:Dystrophin; D014867:Water; D001127:Arginine Vasopressin