Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice

Background/Aims

Pharmacological blockade of the renin–angiotensin system (RAS) attenuates liver fibrogenesis in rats. Here, we provide genetic evidence implicating angiotensin type 1 (AT1) receptors in liver fibrogenesis.

Methods

Wild type (WT) and AT1a knockout [AT1a (−/−)] mice were subjected to either sham operation or bile-duct ligation. Fibrosis was assessed by Sirius Red staining and hydroxyproline hepatic content. Fibrogenic and inflammatory cytokines were measured by ELISA.

Results

Bile duct ligation-induced elevation of serum liver enzymes was similar in WT and AT1a (−/−) mice. Bile duct ligated WT mice showed inflammatory changes and severe septal fibrosis. In contrast, AT1a (−/−) mice showed minor fibrotic lesions. Collagen accumulation was lower in AT1a (−/−) mice compared to WT mice. The increase in hepatic concentration of TGFβ1 and pro-inflammatory cytokines was attenuated in AT1a (−/−) mice compared to WT mice. Immunohistochemistry analysis revealed decreased infiltration by inflammatory cells, lipid peroxidation products as well as decreased phosphorylation of c-Jun and p42/44 MAPK in AT1a (−/−) mice compared to AT1 (+/+) mice.

Conclusions

AT1 receptors play an important role in the development of fibrosis. Pharmacological blockade of AT1 receptors appears to be a promising approach to treat liver fibrosis.

Introduction

The renin–angiotensin system (RAS) plays a major role in the wound healing response to injury [1]. Angiotensin II (Ang II) is synthesized in chronically damaged tissues by resident myofibroblasts [2]. Locally produced Ang II binds to angiotensin type 1 (AT1) receptors to stimulate angiogenesis, recruitment of inflammatory cells, growth of myofibroblasts and synthesis of extracellular matrix proteins [3]. If the remodeling process persists, tissue fibrosis develops. Due to its biological properties, the RAS is a target to prevent fibrosis in chronic inflammatory conditions. The blockade of the RAS, either with angiotensin-converting enzyme (ACE) inhibitors or AT1 antagonists, attenuates fibrosis development in experimental cardiac and renal fibrosis [4] and are widely used as antifibrotic therapy in patients with chronic cardiac and renal diseases [5].

Recent evidence indicates that the RAS is also involved in liver fibrogenesis. A local RAS is expressed in chronically damaged livers, and activated hepatic stellate cells (HSCs), a major fibrogenic cell type, express the components of RAS and synthesize Ang II [6]. Moreover, Ang II exerts powerful inflammatory and fibrogenic effects in cultured HSCs, and the inhibition of Ang II generation and/or the blockade of AT1 receptors markedly attenuate liver fibrosis in experimental models in rats [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. These experimental data indicate that this cytokine may play an important role in liver fibrogenesis. In patients, polymorphisms of regulatory genes of the RAS (i.e. angiotensinogen) confer increased susceptibility to develop liver fibrosis [18]. Based on these data, it has been proposed that the blockade of the RAS is a promising antifibrotic therapy for patients with chronic liver diseases [19].

To more precisely define the role of angiotensin signaling in hepatic fibrogenesis, the current study investigated whether mice lacking AT1a receptors are resistant to develop liver fibrosis. Liver fibrosis development was markedly attenuated in AT1a (−/−) mice compared to WT mice. We propose that AT1 receptors play a major role in the pathogenesis of liver fibrosis and that AT1 receptor blockers are promising antifibrotic therapy for patients with chronic liver diseases.