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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Ammonia 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.

Methods

ALF 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.

Results

Serum 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.

Conclusion

TNF-α promoted the transport of ammonia from the blood to brain tissues and exacerbated the toxic effects of ammonia by upregulating Rhcg.
Literature
1.
Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32:734–9.CrossRefPubMed
2.
Bernal W, Hyyrylainen A, Gera A, Audimoolam VK, McPhail MJ, Auzinger G, et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol. 2013;59:74–80.CrossRefPubMed
3.
Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46:1844–52.CrossRefPubMed
4.
Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology. 1999;29:648–53.CrossRefPubMed
5.
Ott P, Vilstrup H. Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis. 2014;29:901–11.CrossRefPubMed
6.
Ott P, Larsen FS. Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal. Neurochem Int. 2004;44:185–98.CrossRefPubMed
7.
Marini AM, Matassi G, Raynal V, André B, Cartron JP, Chérif-Zahar B. The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast. Nat Genet. 2000;26:341–4.CrossRefPubMed
8.
Huang CH, Liu PZ. New insights into the Rh superfamily of genes and proteins in erythroid cells and nonerythroid tissues. Blood Cells Mol Dis. 2001;27:90–101.CrossRefPubMed
9.
Han KH, Lee HW, Handlogten ME, et al. Expression of the ammonia transporter family member, Rh B glycoprotein, in the human kidney. Am J Physiol Renal Physiol. 2013;304:F972–81.CrossRefPubMedPubMedCentral
10.
Weiner ID, Miller RT, Verlander JW. Localization of the ammonium transporters, Rh B glycoprotein and Rh C glycoprotein, in the mouse liver. Gastroenterology. 2003;124:1432–40.CrossRefPubMed
11.
Handlogten ME, Hong SP, Zhang L, Vander AW, Steinbaum ML, Campbell-Thompson M, et al. Expression of the ammonia transporter proteins Rh B glycoprotein and Rh C glycoprotein in the intestinal tract. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1036–47.CrossRefPubMed
12.
Han KH, Mekala K, Babida V, Kim HY, Handlogten ME, Verlander JW, et al. Expression of the gas transporting proteins, Rh B glycoprotein and Rh C glycoprotein, in the murine lung. Am J Physiol Lung Cell Mol Physiol. 2009;297:L153–63.CrossRefPubMedPubMedCentral
13.
14.
Biver S, Belge H, Bourgeois S, Van Vooren P, Nowik M, Scohy S, et al. A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Nature. 2008;456:339–43.CrossRefPubMed
15.
Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2003;114:188–93.CrossRefPubMed
16.
Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, et al. Infection and systemic inflammation, not ammonia, are associated with grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54:640–9.CrossRefPubMed
17.
Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22:125–38.CrossRefPubMed
18.
Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016;4:CD003044.PubMed
19.
Jiang Q, Jiang X-H, Zheng M-H, Chen Y-P. L-ornithine-L-aspartate in the management of hepatic encephalopathy: a meta-analysis. J Gastroenterol Hepatol. 2009;24:9–14.CrossRefPubMed
20.
Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology. 2009;136:2159–68.CrossRefPubMed
21.
Felipo V. Hepatic encephalopathy: effects of liver failure on brain function. Nat Rev Neurosci. 2013;14:851–8.CrossRefPubMed
22.
23.
Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013;10:522–8.CrossRefPubMed
24.
Odeh M. Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory. Eur J Clin Investig. 2007;37:291–304.CrossRef
25.
Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;5:S7–S20.CrossRefPubMed
26.
Jiang W, Desjardins P, Butterworth RF. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem. 2009;109:485–93.CrossRefPubMed
27.
Streetz K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, et al. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology. 2000;119:446–60.CrossRefPubMed
28.
Duchini A, Govindarajan S, Santucci M, Zampi G, Hofman FM. Effects of tumor necrosis factor-α and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS derived endothelial cells. J Investig Med. 1996;44:474–82.PubMed
29.
Rama Rao KV, Jayakumar AR, Tong X, Alvarez VM, Norenberg MD. Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes. J Neuroinflammation. 2010;7:66.CrossRefPubMedPubMedCentral
30.
Johansson FK, Brodd J, Eklöf C, Ferletta M, Hesselager G, Tiger CF, et al. Identification of candidate cancercausing genes in mouse brain tumors by retroviral tagging. Proc Natl Acad Sci U S A. 2004;101:11334–7.CrossRefPubMedPubMedCentral
31.
Hillmann P, Köse M, Söhl K, Müller CE. Ammonium-induced calcium mobilization in 1321N1 astrocytoma cells. Toxicol Appl Pharmacol. 2008;227:36–47.CrossRefPubMed
32.
Liu Z, Chen Y, Mo R, Hui CC, Cheng JF, Mohandas N, et al. Characterization of human RhCG and mouse Rhcg as novel nonerythroid Rh glycoprotein homologues predominantly expressed in kidney and testis. J Biol Chem. 2000;275:25641–51.CrossRefPubMed
33.
Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009;24:95–102.CrossRefPubMed
34.
Caner T, Abdulnour-Nakhoul S, Brown K, Islam MT, Hamm LL, Nakhoul NL. Mechanisms of ammonia and ammonium transport by rhesus associated glycoproteins. Am J Physiol Cell Physiol. 2015;309:C747–58.CrossRefPubMedPubMedCentral
35.
Bakouh N, Benjelloun F, Cherif-Zahar B, Planelles G. The challenge of understanding ammonium homeostasis and the role of the Rh glycoproteins. Transfus Clin Biol. 2006;13:139–46.CrossRefPubMed
36.
Bakouh N, Benjelloun F, Hulin P, Brouillard F, Edelman A, Cherif-Zahar B, et al. NH3 is involved in the NH4 + transport induced by the functional expression of the human Rh C glycoprotein. J Biol Chem. 2004;279:15975–83.CrossRefPubMed
37.
Bao S, Zhao Q, Zheng J, Li N, Huang C, Chen M, et al. Interleukin-23 mediates the pathogenesis of LPS/GalN-induced liver injury in mice. Int Immunopharmacol. 2017;46:97–104.CrossRefPubMed
38.
Sekiyama KD, Yoshiba M, Thomson AW. Circulating proinflammatory cytokines (IL-1 beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis. Clin Exp Immunol. 1994;98:71–7.CrossRefPubMedPubMedCentral
39.
Streetz K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, et al. Tumour necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology. 2000;119:446–60.CrossRefPubMed
40.
Bernal W, Donaldson P, Underhill J, Wendon J, Williams R. Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol. 1998;29:53–9.CrossRefPubMed
41.
Tsuchiya N, Tokushige K, Yamaguchi N, Hasegawa K, Hashimoto E, Yamauchi K, et al. Influence of TNF gene polymorphism in patients with acute and fulminant hepatitis. J Gastroenterol. 2004;39:859–66.CrossRefPubMed
42.
Habbas S, Santello M, Becker D, Stubbe H, Zappia G, Liaudet N, et al. Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell. 2015;163:1730–41.CrossRefPubMed
43.
Küsters S, Tiegs G, Alexopoulou L, Pasparakis M, Douni E, Künstle G, et al. In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol. 1997;27:2870–5.CrossRefPubMed
44.
Nagaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H. High levels of serum interleukin-10 and tumor necrosis factor-α are associated with fatality in fulminant hepatitis. J Infect Dis. 2000;182:1103–8.CrossRefPubMed
Metadata
Title
Effect of tumor necrosis factor-α on the expression of the ammonia transporter Rhcg in the brain in mice with acute liver failure
Authors
Wen Wang
Hui Lu
Xu Lu
Donglei Wang
Zhaohan Wang
Wenying Dai
Jinyong Wang
Pei Liu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1264-8

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