Expression of Angiotensin II Type 1 Receptor in Rat Hepatic Stellate Cells and Its Effects on Cell Growth and Collagen Production

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Abstract

Objective: To investigate the contribution of angiotensin II towards the process of hepatic fibrosis that is largely due to hepatic stellate cell growth. Methods: Adult rat hepatic stellate cells were cultured and checked for the expression of angiotensin II receptor 1a (AT1a) mRNA by RT-PCR and sequence analysis. The effects of angiotensin II were observed on stimulation of hepatic stellate cell growth detected by MTT assays, 3H-thymidine incorporation and cell count, and collagen synthesis by 3H-proline incorporation. Results: We demonstrated that cultured adult rat hepatic stellate cells expressed AT1a mRNA, and angiotensin II in a concentration-dependent manner stimulated hepatic stellate cell growth at a concentration of 10–7–10–9 mol/l and collagen synthesis at a concentration of 10–6–10–10 mol/l. Also, AT1a receptor antagonist, in a concentration-dependent manner, blocked the cell growth from 10–6 to 10–8 mol/l and collagen synthesis from 10–6 to 10–9 mol/l. Conclusions: The results provided direct evidence that AT1a mRNA was expressed in rat hepatic stellate cells and angiotensin II could contribute towards the development of hepatic fibrosis via AT1a receptor.

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Most cited references 5

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Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.

Christian G. Brilla, Luiz S. Matsubara, Karl T Weber (1993)

In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both the left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 microgram/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antagonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT and AL (202 +/- 12 and 193 +/- 7 mmHg, respectively; P < 0.0005 vs C); it remained elevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVH, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.

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Long-term therapy of chronic hepatitis B with lamivudine.

Marc G Ghany, J Hoofnagle, H. Park … (2000)

Lamivudine therapy induces improvements in chronic hepatitis B in a high proportion of patients, but prolonged therapy is limited by the development of viral resistance. We analyzed clinical responses and virologic resistance in 27 patients treated continuously with lamivudine for 2 to 4 years. Serum transaminases, hepatitis B virus (HBV) DNA by both branched DNA (bDNA) signal amplification and quantitative polymerase chain reaction were monitored at 4- to 8-week intervals. Virologic resistance to lamivudine was confirmed by the presence of mutations in the YMDD motif of the polymerase gene by restriction fragment-length polymorphism analysis. Serum HBV-DNA levels decreased rapidly in all treated patients, falling by 4 to 5 logs within 1 year. Transaminase levels also decreased and were normal in 70% of patients at 1 year, at which point liver histology had improved in 81% of patients. Viral resistance began to emerge after 8 months of therapy, eventually developing in 14 patients, including 76% of hepatitis B e antigen (HBeAg)-positive patients but only 10% of HBeAg-negative patients. Lamivudine withdrawal led to reappearance of wild-type HBV species, but retreatment led to more rapid reappearance of the mutant virus. Clinical, serum biochemical, and histologic improvements were maintained in the 13 patients who did not develop resistance. Thus, long-term therapy with lamivudine resulted in maintained improvements in virologic, biochemical, and histologic features of disease in most patients with HBeAg-negative chronic hepatitis B and in the subgroup of HBeAg-positive patients with high serum transaminase levels. A high rate of resistance limited efficacy, particularly in patients who remained HBeAg positive on therapy.

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Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis.

Hansjörg Schneider-Poetsch, C. Klein, Nicola J Kalk (1999)

Administration of angiotensin II causes an increase in portal pressure, and plasma concentration of angiotensin II is elevated in patients with cirrhosis, suggesting that angiotensin II may be involved in the pathogenesis of portal hypertension in cirrhosis. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Thirty patients with severe (hepatic venous pressure gradient [HVPG] >/= 20 mm Hg) and 15 patients with moderate (HVPG /= 20 mm Hg) and 10 (HVPG < 20 mm Hg), respectively, cirrhotic controls. On the seventh day, HVPG was determined again, and blood pressure, heart rate, body weight, and parameters of liver and kidney function were recorded. Losartan induced a significant (P <.001) decrease of HVPG in the patients with severe (-46.8% +/- 15.5%) and moderate (-44.1% +/- 14.7%) portal hypertension, while no significant change was seen in the controls. Losartan caused a slight but significant (P <.01) fall in mean arterial blood pressure (-3.1 +/- 5.0 and -3.5 +/- 4.3 mm Hg, respectively). One patient treated with losartan had a short symptomatic hypotensive reaction after the first dose of losartan that did not recur despite continued treatment. No deterioration of liver or kidney function was observed. The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2003

Publication date (Print): 2003

Publication date (Electronic): 29 August 2003

Volume: 60

Issue: 3

Pages: 105-110

Affiliations

^aDepartment of Gerontology, LiuHua Bridge Hospital, ^bPLA Institute of Digestive Diseases and ^cDepartment of Cardiology, Nanfang Hospital, The First Military Medical University, and ^dDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Zhongshan University, Guangzhou, PR China

Article

Publisher ID: 72520 Other ID: Horm Res 2003;60:105–110

DOI: 10.1159/000072520

PubMed ID: 12931036

SO-VID: 728ed40b-aa27-417c-b997-99670e8bf93b

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 31 May 2002

Date accepted : 09 April 2003

Page count

Figures: 3, References: 26, Pages: 6

Expression of Angiotensin II Type 1 Receptor in Rat Hepatic Stellate Cells and Its Effects on Cell Growth and Collagen Production

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Karger: Endocrinology

Most cited references 5

Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.

Long-term therapy of chronic hepatitis B with lamivudine.

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis.

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