Digestive Diseases and Sciences

, Volume 58, Issue 5, pp 1271–1281 | Cite as

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

  • Susanne Mende
  • Sigrid Schulte
  • Ingo Strack
  • Heike Hunt
  • Margarete Odenthal
  • Galyna Pryymachuck
  • Maria Quasdorff
  • Münevver Demir
  • Dirk Nierhoff
  • Hans-Peter Dienes
  • Tobias Goeser
  • Hans-Michael Steffen
  • Ulrich Töx
Original Article

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.

Keywords

Abcb4 knockout AT1R-blocker Beta blocker Sclerosing cholangitis Fibrogenesis 

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

Supplementary material

10620_2012_2499_MOESM1_ESM.doc (150 kb)
Supplementary material 1 (DOC 149 kb)

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Susanne Mende
    • 1
  • Sigrid Schulte
    • 1
  • Ingo Strack
    • 2
  • Heike Hunt
    • 2
    • 3
  • Margarete Odenthal
    • 2
  • Galyna Pryymachuck
    • 1
  • Maria Quasdorff
    • 1
  • Münevver Demir
    • 1
  • Dirk Nierhoff
    • 1
  • Hans-Peter Dienes
    • 2
  • Tobias Goeser
    • 1
  • Hans-Michael Steffen
    • 1
  • Ulrich Töx
    • 1
  1. 1.Department of Gastroenterology and HepatologyUniversity Hospital of CologneCologneGermany
  2. 2.Institute for PathologyUniversity Hospital of CologneCologneGermany
  3. 3.Department of PathologyUniversity of North Carolina at Chapel HillChapel HillUSA

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