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Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model

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Abstract

Background

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin–angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models.

Aims

We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model.

Methods

Sixty-five Abcb4−/− mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting.

Results

Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.

Conclusions

Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4−/− mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.

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Abbreviations

α-SMA:

α-Smooth muscle actin

ADR:

Adrenoceptor

Ang II:

Angiotensin II

ACE:

Angiotensin converting enzyme

AT1R:

Angiotensin II type 1 receptor

ARB:

Angiotensin II type 1 receptor blocker

CTGF:

Connective tissue growth factor

CK-19:

Cytokeratin-19

ET-1:

Endothelin-1

ECM:

Extracellular matrix

HSC:

Hepatic stellate cell

MMP:

Matrix metalloproteinase

PSC:

Primary sclerosing cholangitis

PC-α1:

Procollagen α1(I)

RT-PCR:

Real-time quantitative reverse transcription polymerase chain reaction

RAS:

Renin–angiotensin system

SNS:

Sympathetic nervous system

TIMP:

Tissue inhibitor of matrix metalloproteinase

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Acknowledgments

We greatly appreciate the excellent technical assistance of Gudrun Suckau and Brigitta Jacob. We are also indebted to Boehringer Ingelheim GmbH & Co. KG for kindly providing telmisartan. This work was supported by a grant from the Marga and Walter Boll Stiftung.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, University Hospital of Cologne, Kerpenerstrasse 62, 50924, Cologne, Germany

    Susanne Mende, Sigrid Schulte, Galyna Pryymachuck, Maria Quasdorff, Münevver Demir, Dirk Nierhoff, Tobias Goeser, Hans-Michael Steffen & Ulrich Töx

  2. Institute for Pathology, University Hospital of Cologne, Kerpenerstrasse 62, 50924, Cologne, Germany

    Ingo Strack, Heike Hunt, Margarete Odenthal & Hans-Peter Dienes

  3. Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Heike Hunt

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  1. Susanne Mende
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Correspondence to Ulrich Töx.

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Susanne Mende, Sigrid Schulte and Ingo Strack contributed equally to this work.

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Mende, S., Schulte, S., Strack, I. et al. Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model. Dig Dis Sci 58, 1271–1281 (2013). https://doi.org/10.1007/s10620-012-2499-3

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