Sulfonylurea receptor 1 contributes to the astrocyte swelling and brain edema in acute liver failure.
Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation, and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, nonselective cation (NCCa-ATP) channel. We therefore examined its potential role in the astrocyte swelling/brain edema associated with ALF. Cultured astrocytes treated with 5 mM ammonia showed a threefold increase in the sulfonylurea receptor type 1 (SUR1) protein expression, a marker of NCCa-ATP channel activity. Blocking SUR1 with glibenclamide significantly reduced the ammonia-induced cell swelling in cultured astrocytes. Additionally, overexpression of SUR1 in ammonia-treated cultured astrocytes was significantly reduced by cotreatment of cells with BAY 11-7082, an inhibitor of NF-κB, indicating the involvement of an NF-κB-mediated SUR1 upregulation in the mechanism of ammonia-induced astrocyte swelling. Brain SUR1 mRNA level was also found to be increased in the thioacetamide (TAA) rat model of ALF. Additionally, we found a significant increase in SUR1 protein expression in rat brain cortical astrocytes in TAA-treated rats. Treatment with glibenclamide significantly reduced the brain edema in this model of ALF. These findings strongly suggest the involvement of NCCa-ATP channel in the astrocyte swelling/brain edema in ALF and that targeting this channel may represent a useful approach for the treatment of the brain edema associated with ALF.
Department of Pathology, University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL, 33101, USA.
A R
AR
Jayakumar
V
V
Valdes
X Y
XY
Tong
N
N
Shamaladevi
W
W
Gonzalez
M D
MD
Norenberg
D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001929:Brain Edema / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D017114:Liver Failure, Acute / Q000378:metabolism*; D051381:Rats; D064233:Sulfonylurea Receptors / Q000378:metabolism*
C577509:Abcc8 protein, rat; D007004:Hypoglycemic Agents; D007473:Ion Channels; D064233:Sulfonylurea Receptors; C491711:nonselective cation channel protein, rat; D000641:Ammonia; D005905:Glyburide