Elsevier

Hepatology Research

Volume 21, Issue 2, October 2001, Pages 147-158
Hepatology Research

Anti-fibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats

https://doi.org/10.1016/S1386-6346(01)00102-4Get rights and content

Abstract

The tissue renin–angiotensin system has recently been demonstrated to reduce fibrogenesis in various organs. However, little has been clarified regarding its role in hepatic fibrosis. The purpose of this study was to investigate the effect of angiotensin-converting enzyme inhibitors on liver fibrogenesis induced in rats by low-dose chronic carbon tetrachloride administration. We used lisinopril that is absorbed in its active form and not metabolized in the liver to avoid any influence by the administration of the chemical. Carbon tetrachloride was administered twice a week i.p. Twelve and 24 weeks after the start of treatment, expanded periportal fibrosis or portal–portal bridgings and severe fat deposition were observed in the rats treated with carbon tetrachloride alone, and these findings were significantly reduced with the simultaneous treatment with lisinopril. The hydroxyproline content of the liver was significantly lower in the lisinopril-treated group. Angiotensin II up-regulated mRNA of pro α (I) collagen and transforming growth factor-β in isolated hepatic stellate cells. These results suggest that the local tissue renin–angiotensin system plays a role in rat hepatic fibrogenesis induced by chronic carbon tetrachloride administration and that hepatic fibrogenesis is significantly reduced by ACE inhibitors.

Introduction

The renin–angiotensin-aldosterone system plays an important role in the regulation of the systemic blood pressure, body fluid and electrolyte balance. Moreover, angiotensin-converting enzyme (ACE) inhibitors have been developed to block the renin–angiotensin system and reduce systemic blood pressure. On the other hand, the existence of a local tissue renin–angiotensin system has been recently postulated [1], and its existence is actually supported by the fact that the expressions of the mRNA set of angiotensinogen, renin, and ACE has been detected in various local tissues and/or organs [2]. Recently, a variety of physiological roles of angiotensin II (Ang II) have been clarified not only in the pathogenesis and maintenance of high blood pressure [3] but also in the stimulation of fibroblast proliferation and collagen synthesis by non-parenchymal cells [4], [5], [6]. Decrease in the levels of serum fibrosis markers and the amounts of collagen in cardiac muscle [7], inhibition of pulmonary fibrogenesis in irradiated rats [8] and improvement of proteinuria and glomerular lesions [9] have been achieved by the administration of ACE inhibitors. These inhibitory effects on fibrogenesis are tissue-specific and localized, indicating that Ang II functions independently in every tissue or organ in a paracrine or autocrine manner.

Hepatic fibrosis is a common pathological feature of progressive chronic liver diseases, and is characterized by an abnormal increase in extracellular matrices. The increased extracellular matrices mechanically interfere with blood flow and reduce liver functions. The most important cells directly related to hepatic fibrosis are hepatic stellate cells (HSCs, Ito cells) distributed in Disse's cavity [10], [11], [12]. When hepatic parenchymal cells are disturbed, HSCs enlarge, proliferate, and transform into myofibroblasts. These transformed HSCs locally synthesize and excrete a variety of extracellular matrices and promote hepatic fibrosis [13]. Non-parenchymal cell transformation into myofibroblasts has been demonstrated in every organ of the body, e.g., renal mesangial cells [14], and interstitial cells in the myocardium [15] in which Ang II stimulates fibrosis in kidneys and the heart, respectively. This pivotal role of the tissue renin–angiotensin system has also been postulated for the fibrogenesis of the liver, but it is not yet fully understood.

In this study, we clarified the role of the tissue renin–angiotensin system in hepatic fibrogenesis by using an ACE inhibitor in a rat model of liver fibrosis induced by a treatment with chronic carbon tetrachloride (CCl4). We also examined the role of Ang II in HSCs in vitro. The results showed that the renin–angiotensin system exacerbates hepatic fibrosis and that CCl4-induced hepatic fibrogenesis was inhibited by an ACE inhibitor.

Section snippets

Animals

All animal experiments were approved by the Animal Experimentation Committee of the School of Medicine, Keio University. Male Sprague–Dawley rats weighing 180–220 g were used throughout the experiments. All animals were housed under specific pathogen-free conditions in cages and were acclimated to the housing situation for one week before the experiments. Two rats were housed to a cage and given a commercial diet in pellet form.

Administration of CCl4 and lisinopril

CCl4 (ultra pure grade, Kanto Kagaku, Tokyo, Japan) was dissolved

In vivo experimental model

The body weight and the liver weight of each rat did not significantly differ between four experimental groups.

Histopathological comparison was made between the experimental groups. Fig. 1 shows Silver staining of the histology at 8, 12, and 24 weeks. No significant histological changes were detected in the lisinopril only group at any time during the experiment. A histological examination of livers obtained 8 weeks after the start of treatment showed diffuse fat deposition in hepatocytes and

Discussion

The inhibition of hepatic fibrosis is ultimately beneficial in preventing the progression of chronic liver diseases such as chronic viral or alcoholic hepatitis and liver cirrhosis. Potential inhibitors of hepatic fibrosis, including dexamethasone [25], interferon γ [26], colchicines [27], and 16,16-dimethyl prostaglandin E2 [28], have been reported, but none of them has been successfully used for the treatment of patients. One of the ACE inhibitors, captopril, has been well studied and

Acknowledgements

This work was partially supported by a grant from the Japanese Ministry of Education, Science and Culture and from Keio University.

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