AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl4

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Abstract

The renin–angiotensin system has been shown to contribute to fibrogenesis in varieties of organs, including the liver. Here, we investigated whether the angiotensin II type 1A receptor (AT1A) is implicated in the development of liver fibrosis, using AT1A-deficient and wild-type (WT) mice. After single dose of carbon tetrachloride (CCl4), there were no significant differences between two groups with regard to hepatic inflammation and necrosis. After 4 weeks of treatment with CCl4, histological examination revealed that AT1A-deficient mice showed less infiltration of inflammatory cells and less severe progression of liver fibrosis compared with WT mice. These findings were accompanied by the hepatic content of hydoxyproline and the expression of α-smooth muscle actin (αSMA). The level of transforming growth factor-β1 (TGF-β1) messenger RNA was markedly higher in WT mice when compared with AT1A-deficient mice. These results confirm that signaling via AT1A plays a pivotal role in hepatic fibrogenesis.

Section snippets

Materials and methods

Animals. AT1A-deficient mice were established by Sugaya et al. [12], and a kind gift from Tanabe Seiyaku (Osaka, Japan) and C57BL/6 mice were obtained from Hiroshima Jikken Doubutsu (Hiroshima, Japan). Both strains of mice have the same genetic background and animals aged 6–8 weeks were used in the present study. The mice were allowed free access to food and water, and were housed at a constant temperature with a 12-h light/dark cycle during the study. To assess the necrotic and inflammatory

AT1 mRNA expression

To confirm the absence of AT1 receptors in AT1A-deficient mice, RT-PCR was performed to evaluate hepatic mRNA levels of AT1. The expression of AT1 mRNA was not observed in the liver of AT1A-deficient mice, whereas it was seen in that of WT mice (Fig. 1).

Parameters of necrosis/inflammation

To determine whether absence of the AT1A receptor had any influence on necrosis and inflammation caused by acute exposure to CCl4, serum transaminases and the proinflammatory cytokine TNF-α were measured. There were no significant differences of

Discussion

In the cardiovascular system and the kidneys, blockade of Ang II has been shown to prevent fibrosis and inflammatory cell infiltration [19], [20], [21], [22]. Ang II could also be involved in the process of fibrogenesis because of its action as a proinflammatory cytokine, participating in various steps of the inflammatory response. Interestingly, systemic infusion of Ang II results in significant cardiac and renal fibrosis, but no fibrotic response occurs in the liver [23].

Previous in vitro

Acknowledgements

The authors thank Dr. Takeshi Sugaya (Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Osaka) for providing the Angiotensin II type 1A receptor-deficient mice. This study was partly supported by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology to Dr. Tazuma (No. 12670489).

References (34)

  • M. Ruiz-Ortega et al.

    ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritis

    Kidney Int.

    (1995)
  • G. Paizis et al.

    Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis

    J. Hepatol.

    (2001)
  • J. Shi et al.

    Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride

    Am. J. Pathol.

    (1998)
  • T. Knittel et al.

    Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair

    Am. J. Pathol.

    (1999)
  • A.A. Lee et al.

    Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts

    J. Mol. Cell. Cardiol.

    (1995)
  • G. Ballardini et al.

    Desmin and actin in the identification of Ito cells and in monitoring their evolution to myofibroblasts in experimental liver fibrosis

    Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.

    (1988)
  • Z. Zhu et al.

    Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice

    Hypertension

    (1998)
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