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

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.

Taurine transporter (TauT) deficiency impairs ammonia detoxification in mouse liver

“…However, TNFα, whose plasma levels are elevated seven-to eightfold in 9-to 15-mo-old TauT KO animals (17), may trigger up-regulation of RhCG in mouse liver. In line with this, elevated TNFα was shown to up-regulate RhCG in vascular endothelial cells in mouse brain in acute liver failure (31). On the other hand, RhCG expression was not significantly increased in livers from 3-mo-old TauT KO mice (SI Appendix, Fig.…”

Could protein content of Urinary Extracellular Vesicles be useful to detect Cirrhosis in Alcoholic Liver Disease?

“…Indeed, ferroptosis-inducing therapy is being applied as treatment in many cancers by using drugs such as sorafenib, erastin and RSL3 66 , and new formulations with erastin-loaded exosomes are been explored 67 . Other upregulated uEV-proteins involved in homeostasis of molecules are RHCG, that plays a major role in transporting ammonia and accumulates in acute liver failure, resulting in brain damage 68 , 69 ; and GDPD3, responsible for lysophosphatidic acid synthesis that, in turns, is involved in liver disease development 70 - 72 .…”

Could Protein Content of Urinary Extracellular Vesicles be Useful to Detect Alcoholic Liver Disease and Assess Hepatocarcinoma Risk?

“…Indeed, ferroptosis-inducing therapy is being applied as treatment in many cancers by using drugs such as sorafenib, erastin and RSL3 [89], and new formulations with erastin-loaded exosomes are been explored [90]. Other upregulated uEV-proteins involved in homeostasis of molecules are RHCG, that plays a major role in transporting ammonia and accumulates in acute liver failure, resulting in brain damage [91,92]; and GDPD3, responsible for lysophosphatidic acid synthesis that, in turns, is involved in liver disease development [93][94][95].…”