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

Autor: Vitaly I. Pozdeev, Elisabeth Lang, Boris Görg, Hans J. Bidmon, Prashant V. Shinde, Gerald Kircheis, Diran Herebian, Klaus Pfeffer, Florian Lang, Dieter Häussinger, Karl S. Lang, Philipp A. Lang
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-017-07640-8
Popis: 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.
Databáze: Directory of Open Access Journals
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