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 journalArticle

33 Citations (Scopus)

Abstract

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
Pages (from-to)272-278
Number of pages7
JournalJournal of Hepatology
Volume54
Issue number2
DOIs
StatePublished - Feb 1 2011

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Sodium-Potassium-Chloride Symporters
Acute Liver Failure
Brain Edema
Thioacetamide
Astrocytes
Bumetanide
Brain
Western Blotting
Water
Intracranial Pressure
Ammonia
Proteins
Phosphorylation

Keywords

  • Brain edema
  • Liver failure
  • NKCC

ASJC Scopus subject areas

  • Hepatology

Cite this

The Na-K-Cl cotransporter in the brain edema of acute liver failure. / Jayakumar, Arumugam R.; Valdes, Vanessa; Norenberg, Michael D.

In: Journal of Hepatology, Vol. 54, No. 2, 01.02.2011, p. 272-278.

Research output: Contribution to journalArticle

Jayakumar, Arumugam R. ; Valdes, Vanessa ; Norenberg, Michael D. / The Na-K-Cl cotransporter in the brain edema of acute liver failure. In: Journal of Hepatology. 2011 ; Vol. 54, No. 2. pp. 272-278.
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