TNFα 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 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.