Effect of tumor necrosis factor-\u03b1 on the expression of the ammonia transporter Rhcg in the brain in mice with acute liver failure

Wen Wang,Hui Lu,Wenying Dai,Pei Liu,Zhaohan Wang,Donglei Wang,Xu Lu,Jinyong Wang

doi:10.1186/s12974-018-1264-8

Abstract

BackgroundAmmonia and tumor necrosis factor-alpha (TNF-α) play important roles in the mechanisms of hepatic encephalopathy (HE). Rhesus glycoprotein C (Rhcg) is important for ammonia transport especially in the kidney. The aim of the present study was to investigate the role of Rhcg in the brain in acute liver failure (ALF) and the effect of TNF-α on Rhcg expression.MethodsALF mouse models were generated by treatment with d-galactosamine (D-GalN) and lipopolysaccharide (LPS), or D-GalN and TNF-α. ALF induction was blocked by pretreatment with anti-TNF-α IgG. The levels of serum TNF-α were determined by ELISA. Blood ammonia and brain ammonia concentrations were detected using an ammonia assay kit. The expression and distribution of Rhcg in the brain tissues of ALF mice were examined by western blotting, real-time PCR, immunohistochemical, and immunofluorescence analyses.ResultsSerum TNF-α levels were increased in the LPS/D-GalN group. Blood and brain ammonia were increased in the LPS/D-GalN- and TNF-α/D-GalN-induced ALF groups. Rhcg mRNA and protein levels were elevated in both ALF groups, consistent with the increase in blood and brain ammonia. Rhcg was mainly expressed in vascular endothelial cells and astrocytes. Pretreatment with anti-TNF-α IgG antibody downregulated Rhcg in brain tissues in the LPS/D-GalN group, prevented the occurrence of ALF, and reduced blood and brain ammonia levels in the LPS/D-GalN group.ConclusionTNF-α promoted the transport of ammonia from the blood to brain tissues and exacerbated the toxic effects of ammonia by upregulating Rhcg.

Highlights

Ammonia and tumor necrosis factor-alpha (TNF-α) play important roles in the mechanisms of hepatic encephalopathy (HE)
In conclusion, the ammonia transporter Rhcg was expressed in brain tissues of C57BL/6 mice
Brain Rhcg expression was increased in LPS/D-GalN- and TNF-α/D-GalN-induced acute liver failure (ALF) mice and correlated with the blood and brain ammonia concentration

Summary

Introduction

Ammonia and tumor necrosis factor-alpha (TNF-α) play important roles in the mechanisms of hepatic encephalopathy (HE). The aim of the present study was to investigate the role of Rhcg in the brain in acute liver failure (ALF) and the effect of TNF-α on Rhcg expression. Acute liver failure (ALF) is the clinical manifestation of sudden and severe hepatic injury and arises from many causes. ALF patients develop hepatic encephalopathy (HE) and subsequently symptomatic cerebral edema (CE), which progresses to intracranial hypertension. In patients with ALF, the plasma concentrations of ammonia are drastically elevated and related to the development of brain edema and herniation [3, 4]. A longstanding hypothesis proposes that the development of CE is related to the cerebral uptake of ammonia from the blood and subsequent disturbance of

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