title: Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure.
abstract: Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6% ± 0.3 and 2.3 ± 0.4%, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF.
authors: Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33101, USA. Electronic address: vkakulavarapu@med.miami.edu.
authors: Kakulavarapu V
authors: KV
authors: Rama Rao
authors: Department of Medicine, University of California, San Francisco, CA 94143, USA; Department of Physiology, University of California, San Francisco, CA 94143, USA.
authors: A S
authors: AS
authors: Verkman
authors: Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Veterans Affairs Medical Center, Miami, FL 33125, USA.
authors: Kevin M
authors: KM
authors: Curtis
authors: Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Veterans Affairs Medical Center, Miami, FL 33125, USA. Electronic address: mnorenbe@med.miami.edu.
authors: Michael D
authors: MD
authors: Norenberg
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency* / Q000235:genetics; D001927:Brain Diseases / Q000209:etiology* / Q000235:genetics; D001929:Brain Edema / Q000209:etiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D017114:Liver Failure, Acute / Q000150:complications*; D051379:Mice; D008822:Mice, Transgenic; D013853:Thioacetamide / Q000633:toxicity; D013997:Time Factors
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; D013853:Thioacetamide; D000082:Acetaminophen
keywords: Acetaminophen; Acute liver failure; Aquaporin-4; Astrocyte swelling; Brain edema; Thioacetamide; Transgenic mice