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TNFα induced up-regulation of Na(+),K(+),2Cl(-) cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity.

TNFα induced up-regulation of Na(+),K(+),2Cl(-) cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity.
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Pozdeev VI, Lang E, Görg B, Bidmon HJ, Shinde PV, Kircheis G, Herebian D, Pfeffer K, Lang F, Häussinger D, Lang KS, Lang PA,


Pozdeev VI, Lang E, Görg B, Bidmon HJ, Shinde PV, Kircheis G, Herebian D, Pfeffer K, Lang F, Häussinger D, Lang KS, Lang PA, (click to view)

Pozdeev VI, Lang E, Görg B, Bidmon HJ, Shinde PV, Kircheis G, Herebian D, Pfeffer K, Lang F, Häussinger D, Lang KS, Lang PA,

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Scientific reports 2017 08 117(1) 7938 doi 10.1038/s41598-017-07640-8
Abstract

The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4(+). Cellular NH4(+) uptake is accomplished mainly by the Na(+),K(+),2Cl(-) cotransporter. Here we show that hepatic clearance of NH4(+) is impaired in TNFα deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4(+), TNFα deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4(+) load, virtually all TNFα deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFα treatment of wild type mice sensitized the animals to the toxic effects of an NH4(+) load. The protection of TNFα-deficient mice against an NH4(+) load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFα formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.

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