TNF? induced up-regulation of Na⁺,K⁺,2Cl^- cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity.

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 TNF? deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH₄⁺, TNF? 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 TNF? deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNF? treatment of wild type mice sensitized the animals to the toxic effects of an NH₄⁺ load. The protection of TNF?-deficient mice against an NH₄⁺ load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNF? formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.

SUBMITTER: Pozdeev VI 

PROVIDER: S-EPMC5554233 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature