The Na-K-Cl cotransporter in the brain edema of acute liver failure

Arumugam R. Jayakumar, Vanessa Valdes, Michael D. Norenberg

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Background & Aims: 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.

Original languageEnglish (US)
Pages (from-to)272-278
Number of pages7
JournalJournal of Hepatology
Issue number2
StatePublished - Feb 2011


  • Brain edema
  • Liver failure
  • NKCC

ASJC Scopus subject areas

  • Hepatology


Dive into the research topics of 'The Na-K-Cl cotransporter in the brain edema of acute liver failure'. Together they form a unique fingerprint.

Cite this