Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis

Schulte, Sigrid; Oidtmann, Annika; Kociok, Norbert; Demir, Münevver; Odenthal, Margarete; Drebber, Uta; Dienes, Hans‐Peter; Nierhoff, Dirk; Goeser, Tobias; Toex, Ulrich; Steffen, Hans‐Michael

doi:10.1111/j.1478-3231.2008.01902.x

Cited by 13 publications

(13 citation statements)

References 35 publications

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“…In contrast, genes mainly expressed by hepatocytes (i.e., cytochrome P-450 2E1) and AT1 receptors were downregulated in CHC livers compared with normal livers. These findings are in agreement with previous reports on hepatic gene expression in patients with CHC (2,36). Components of the NOX complex (NOX-4, Rac-1, and Rac-2) were upregulated in livers with chronic HCV infection.…”

Section: Baseline Characteristics Of the Patientssupporting

confidence: 83%

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Colmenero

Bataller

Sancho‐Bru

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

113

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Colmenero J, Bataller R, Sancho-Bru P, Domínguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Ginès P. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297: G726 -G734, 2009. First published July 23, 2009 doi:10.1152/ajpgi.00162.2009.-Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/ day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen ␣1(I) and ␣1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.angiotensin; liver fibrosis; antifibrogenic ACCUMULATING EVIDENCE INDICATES that the renin-angiotensin system (RAS) is a major mediator in liver fibrogenesis. Key components of the RAS are locally expressed in chronically injured livers and activated hepatic stellate cells de novo generate angiotensin II (5), the main effector peptide of this system. Angiotensin II induces an array of fibrogenic actions in hepatic stellate cells (HSC) including cell proliferation, migration, secretion of proinflammatory cytokines, and collagen synthesis (34). The fibrogenic and inflammatory actions of angiotensin II in the liver are largely mediated by angiotensin type 1 (AT1) receptors (5). The production of intracellular reactive oxygen species generated by the nonphagocytic NADPH oxidase (NOX) complex is a key event in the angiotensin II-mediated fibrogenesis (...

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Section: Baseline Characteristics Of the Patientssupporting

confidence: 83%

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Colmenero

Bataller

Sancho‐Bru

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

113

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“…hepatocytes [13,28], and Ang II induces CRP production by AT1 receptor in VSMCs, HAECs and macrophages [16,17,18]. Therefore, Ang II possibly regulates the inflammatory response of hepatocytes via Ang II receptors.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

Zhao

Liu

Pang

et al. 2013

Cell Physiol Biochem

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Background: C-reactive protein (CRP) participates in development of inflammatory diseases. Hepatocytes are a major contributor of circulating CRP. Although angiotensin II (Ang II) is known to evoke inflammatory response, it remains unknown whether Ang II induces CRP expression in hepatocytes. The present study observed effect of Ang II on CRP expression and the related signal pathway in hepatocytes. Methods: mRNA and protein expressions in human hepatocytes were determined with RT-PCR and Western blot respectively. Reactive oxygen species (ROS) was measured using a fluorescence probe. CRP in liver and serum of rats was determined by immunohistochemistry and ELISA respectively. Results: Ang II induced mRNA and protein expression of CRP in hepatocytes and increased CRP production in liver and CRP level in serum. Losartan reduced Ang II- induced CRP expression in hepatocytes. Losartan and thenoyltrifluoroacetone decreased Ang II-stimulated ROS production. N-acetylcysteine antagonized Ang II-induced CRP expression. Losartan and N-acetylcysteine inhibited Ang II-activated ERK1/2. Unlike ERK1/2, only losartan inhibited Ang II-activated JNK. Furthermore, pyrrolidine dithiocarbamate abolished Ang II-induced CRP expression. Conclusion: Ang II has ability to induce CRP expression in hepatocytes in vitro and in vivo through AT1 receptor followed by ROS, MAPK and NF-κB signal pathway.

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“…The tumors were immunohistochemically analyzed for the expression of Kit (CD117), CD34, smooth muscle actin (SMA), S-100, desmin, vimentin and Ki-67. Immunohistochemistry was performed as previously described (44,45) using the ABC method based on the epitope labeling by the avidin-biotin peroxidase complex. Diaminobenzidine was used as the chromogen for immunostaining development.…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of miR-221 and miR-222 correlates with pronounced Kit expression in gastrointestinal stromal tumors

Koelz

2011

Int J Oncol

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Abstract. Gastrointestinal stromal tumors (GISTs), are characterized by mutations of the KIT or platelet-derived growth factor receptor-· gene and the constitutive expression of Kit, which is currently being studied as a potential therapeutic target. In this study, we addressed the question of whether the microRNA (miRNA) 221/222 cluster (miR-221/ 222), which has been shown to be dysregulated in many malignancies, is linked to GIST diagnosis and prognosis, and whether it could provide a basis for possible therapeutic approaches. We analyzed the expression of miR-221 and miR-222 in 54 formalin-fixed and paraffin-embedded GISTs and corresponding peripheral non-tumorous tissue by realtime PCR. The miRNA-expression levels were studied in relation to histomorphological parameters, KIT mutation status and immunohistochemical Kit expression. miR-221 and miR-222, were reduced in most of the GISTs, in contrast to other tumors. No correlation was observed between miR-221/ 222 expression levels and histomorphological parameters, tumor risk grade, or KIT mutation status. However, we found major differences in miRNA expression among the different groups of immunohistochemical Kit expression, especially between Kit-negative and -positive tumors. The expression levels of miR-221 and miR-222 were significantly repressed in Kit-positive GISTs, compared to normal tissue, whereas Kit-negative GISTs exhibited a completely inverse expression pattern. This study shows for the first time that miR-221 and miR-222 can act as regulators of Kit expression in GISTs and hence reveals a new aspect in the molecular pathogenesis of these tumors. Although miR-221/222 expression does not have an impact on diagnostics, it could be considered as a tool for future therapeutic strategies for GISTs, especially for tumors with secondary resistance to tyrosine kinase inhibitors.

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Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis

Abstract: In conclusion, AT1R expression is downregulated in human liver cirrhosis specimens because of the reduced expression levels on hepatocytes. Therefore, antifibrogenic therapy with AT1R blockers may be most promising if initiated during early stages of fibrosis.

Cited by 13 publications

References 35 publications

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

Down-regulation of miR-221 and miR-222 correlates with pronounced Kit expression in gastrointestinal stromal tumors

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Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis

Abstract: In conclusion, AT1R expression is downregulated in human liver cirrhosis specimens because of the reduced expression levels on hepatocytes. Therefore, antifibrogenic therapy with AT1R blockers may be most promising if initiated during early stages of fibrosis.

Cited by 13 publications

References 35 publications

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-&#954;B Signal Pathway in Hepatocytes

Down-regulation of miR-221 and miR-222 correlates with pronounced Kit expression in gastrointestinal stromal tumors

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Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes