The Na-K-Cl cotransporter in the brain edema of acute liver failure.
OBJECTIVE
Astrocyte swelling and brain edema associated with increased intracranial pressure are major complications of acute liver failure (ALF). The mechanism for such astrocyte swelling/brain edema, however, is not well understood. We recently found that ammonia, a key etiological factor in ALF, caused the activation of the Na-K-Cl cotransporter-1 (NKCC1) in cultured astrocytes, and that inhibition of such activation led to a reduction in astrocyte swelling, suggesting that NKCC1 activation may be an important factor in the mechanism of brain edema in ALF. To determine whether NKCC activation is also involved in brain edema in vivo, we examined whether NKCC activation occurs in the thioacetamide (TAA) rat model of ALF and determined whether treatment with the NKCC inhibitor bumetanide reduces the severity of brain edema in TAA-treated rats.


METHODS
Brain water content was measured using the gravimetric method. NKCC1 phosphorylation and protein expression were measured by Western blots. NKCC activity was measured in brain cortical slices.


RESULTS
NKCC activity was elevated in brain cortical slices of TAA-treated rats as compared to sham animals. Western blot analysis showed significant increases in total as well as phosphorylated (activated) NKCC1 protein expression in the cortical tissue. These findings were associated with a significant increase in brain water content which was attenuated by treatment with the NKCC inhibitor bumetanide.


CONCLUSIONS
Our studies suggest the involvement of NKCC in the development of brain edema in experimental ALF, and that targeting NKCC may represent a useful therapeutic strategy in humans with ALF.
Department of Pathology, University of Miami, School of Medicine, Miami, FL 33101, USA.
Arumugam R
AR
Jayakumar
Vanessa
V
Valdes
Michael D
MD
Norenberg
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology*; D002034:Bumetanide / Q000494:pharmacology; D017114:Liver Failure, Acute / Q000150:complications*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2; D013853:Thioacetamide / Q000494:pharmacology
C578877:SLC12A2 protein, human; C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D013853:Thioacetamide; D002034:Bumetanide