Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats

Abstract

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II) has been suggested to play an important role in liver fibrogenesis. It induces hepatic stellate cell (HSC) proliferation and up-regulates the transforming growth factor 1 (TGF-1) expression via AT-II type 1 receptor (AT 1-R) in vitro. The aim of the present study was to examine the in vivo effect of candesartan (CA), a clinically used AT 1-R blocker (ARB), and perindopril (PE), an angiotensin-converting enzyme (ACE) inhibitor (ACE-I), on pig serum-induced liver fibrosis development in rats. The clinically available comparable doses of CA and PE significantly attenuated the fibro-sis development. These inhibitory effects of PE and CA were also found in the ongoing liver fibrosis model. The hepatic hydroxyproline and serum fibrosis markers were significantly suppressed by CA and PE treatment. Furthermore, the smooth muscle actin (-SMA) positive cells in number were markedly suppressed by CA and PE treatment. Similarly , the hepatic TGF-1 protein and messenger RNA (mRNA) levels were significantly suppressed. Our in vitro study showed that AT-II increased the TGF-1 mRNA expression in the activated HSCs, and this effect was totally blocked by CA. These results suggested that the RAS, especially AT-II and AT 1-R interaction plays a pivotal role in liver fibrosis development through HSC activation. Because both CA and PE are widely used in clinical practice without serious side effects, these drugs may provide an effective new strategy for anti-liver fibrosis therapy. (HEPATOLOGY 2001; 34:745-750.) The renin-angiotensin system (RAS) is reportedly activated in patients with chronic liver diseases, such as cirrhosis. 1-3 Angiotensin-II (AT-II), which is an octapeptide produced mainly by proteolytic cleavage of its precursor AT-I by angio-tensin-converting enzyme (ACE), has many physiologic effects , including vascular hormonal secretion, tissue growth, and neuronal activities. 4,5 AT-II is also considered a potential mediator of intrahepatic portal hypertension, because its plasma level was increased in patients with cirrhosis, and its administration induced elevation of the portal pressure. 6,7 To date, several types of AT-II receptors have been identified. 5 The AT-II type 1 receptor (AT 1-R) mediates most of the biological effects of AT-II, including increase in the intracellular Ca 2 concentration, cell contraction, and proliferation. 5 Recently , losartan, which is used clinically as an AT 1-R antagonist , has been shown to reduce the portal pressure in hepatic cirrhosis. 8 It has been revealed that AT-II induced contraction and proliferation of hepatic stellate cells (HSCs). 9 AT-II also increased the transforming growth factor 1 (TGF-1) and collagen-I gene expression in the fibroblasts in vitro. 10-12 These biological actions were mediated predominantly through AT 1-R. Accordingly, AT-II and AT 1-R interaction seems to have a pivotal role in liver fibrosis development. Evidence that these mole...

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

“…We previously reported that simultaneous administration of pig serum and either STI-571 or ACE-I significantly inhibited liver fibrosis development (19,20). The pig serum model is known to induce liver fibrosis without severe inflammation (20).…”

“…AT-II is a potent inducer of TGF-ß synthesis through Smad2 in cultured HSCs in vitro (26,27). AT-II induces HSC proliferation and up-regulates TGF-ß expression via the AT1-R pathway (20). The increase in hepatic concentration of TGF-ß induced by bile duct ligation was attenuated in AT1-R knockout mice (28).…”

“…It has been reported that angiotensin-II (AT-II) mediated modulation of TGF-ß ligand expression. AT-II increased TGF-ß gene expression in a dose-dependent manner in activated HSCs in vitro (20). We and others reported that suppression of AT-II by ACE-I markedly attenuated experimental liver fibrosis development and suppressed TGF-ß (3,20).…”

“…The doses of STI-571 and ACE-I were 5 and 2 mg/kg/day by daily gavage, respectively. The doses of these agents were almost comparable to those used in clinical practice (19,20). Rats that received only corn oil were examined as a negative control group.…”

Hypertension and fatty liver: guilty by association?

“…There are three PPARs, whose general effects are to promote fatty acid catabolism in non-adipose tissue and stimulate fatty acid storage in adipose tissue. 65 Animal models have also suggested a potential role for angiotensin II in the progression of NAFLD to hepatic fibrosis, 66 and the use of angiotensin II type 1 receptor antagonists has been shown to reduce this progression. 67 …”