Up-regulation of components of the renin-angiotensin system in the bile duct–ligated rat liver

Paizis, G.; Cooper, Mark E.; Schembri, J. M.; Tikellis, Christos; Burrell, Louise M.; Angus, Peter W

doi:10.1053/gast.2002.36561

Cited by 187 publications

(217 citation statements)

References 29 publications

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“…Thus, our data add to the evidence that delaying the fibrotic process because of b-blockade is not only a matter of inhibition of the fibrogenic properties of HSC but also a more general phenomenon. In contrast to portal fibrotic lesions due to chronic viral or other cholestatic liver diseases, in which portal myofibroblasts are the main fibrogenic cell types, 26,27 in both human PSC and experimental sclerosing cholangitis, only small numbers of periportal myofibroblasts are present. Myofibroblasts of PSC are mainly distributed in the immediate vicinity of sclerosing areas around the bile ducts.…”

Section: Discussionmentioning

confidence: 87%

“…35 In addition, an indirect effect on fibrosis is also suggested because the RAS is highly controlled by the SNS. Paizis et al have reported that angiotensinogen, renin and ACE expression is strongly upregulated during fibrogenesis, 26,27 and high systemic levels of angiotensin II have been shown to exacerbate liver fibrosis. 26 Here, we demonstrate that propranolol treatment leads to a decreased angiotensinogen expression in experimental sclerosing cholangitis.…”

Section: Discussionmentioning

confidence: 99%

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β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Strack

Schulte

Varnholt

et al. 2011

Laboratory Investigation

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Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra-and extrahepatic bile ducts. Until now, no effective medical therapy exists. To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the b-adrenoceptors, we used the Mdr2 À/À mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2 À/À mice untreated or treated with the b-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for a-smooth muscle actin (a-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-b, TNF-a, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2 À/À mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2 À/À mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the b-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-a, TGF-b, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis. Therefore, the blockade of b-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Strack

Schulte

Varnholt

et al. 2011

Laboratory Investigation

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“…These effects of Ang II appear independent of the underlying source of injury and have been documented in settings as diverse as bile-duct stenosis and CCl 4 poisoning (7,8). Consequently, it is thought that Ang II is an amplifier of the general inflammatory response to chronic liver injury but plays a particularly critical role because all components of the local renin-angiotensin system are dramatically up-regulated in the setting of liver injury, leading to excess local production of Ang II (12,13).…”

mentioning

confidence: 99%

CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

McAllister-Lucas¹,

Ruland

Siu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

160

159

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Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang II results from activation of the proinflammatory NF-B transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-B, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-B activation in hepatocytes. In addition, Bcl10 ؊/؊ mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-B through ubiquitination of IKK␥, the regulatory subunit of the I B kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-B transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system. G protein-coupled receptor ͉ hepatocyte ͉ IkB kinase ͉ inflammation ͉ ubiquitination

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“…Activated HSCs produce AngII in vitro and in vivo (40,41). AngII induces hepatic inflammation and stimulates an array of fibrogenic actions in activated HSCs, including cell proliferation, cell migration, secretion of proinflammatory cytokines, and collagen synthesis (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ down-regulates expression of tumor necrosis factor-α converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats

Fujita

Maesawa²,

Oikawa³

et al. 2006

Int J Mol Med

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Abstract. Interferon-Á (IFN-Á) is a potent cytokine that exerts antiproliferative and antifibrogenic effects on hepatic stellate cells (HSCs). Although therapeutic application of IFN-Á for chronic liver diseases is anticipated, the responses of activated HSCs to IFN-Á have not been fully elucidated. To seek unknown molecules and pathways that might be responsive to IFN-Á treatment in activated HSCs, we examined global protein expression profiles using two-dimensional gel electrophoresis combined with peptide mass fingerprint. We identified 76 increased and 59 decreased spots (>3-fold increase or decrease, total 135 spots). Database analysis suggested that the following four pathways were involved in alteration of HSCs toward a quiescent phenotype in response to IFN-Á: i) down-regulation of the TGF-ß and PDGF signaling pathways; ii) reorganization of intermediate filaments; iii) up-regulation of fatty acid metabolism; iv) decreased expression of TNF-· converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17), which is responsible for shedding of the proinflammatory cytokine TNF-·. We confirmed down-regulation of both ADAM17 expression and soluble TNF-· secretion by Western blotting and real-time PCR. TNF-· mRNA/protein expression was not altered by IFN-Á treatment. Our data suggest that IFN-Á stimulation suppresses the activated phenotype of HSCs in vitro through multiple pathways. Of these pathways, down-regulation of ADAM17 expression may play a role in blocking the auto-activation mechanism of cultured HSCs through activation of the TNF-· signaling and shedding pathways.

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Up-regulation of components of the renin-angiotensin system in the bile duct–ligated rat liver

Cited by 187 publications

References 29 publications

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

Interferon-γ down-regulates expression of tumor necrosis factor-α converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats

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