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Blockade of renin-angiotensin system in antifibrotic therapy

Hitoshi Yoshiji1, Shigeki Kuriyama, Hiroshi Fukui

  • 1Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp

Journal of Gastroenterology and Hepatology
|August 25, 2007
PubMed

Insights

The renin-angiotensin system (RAS) drives liver fibrosis by activating hepatic stellate cells. Blocking angiotensin-II (AT-II) with ACE inhibitors or ARBs, especially combined with interferon, shows promise for antifibrosis therapy.

Area of Science:

  • Hepatology
  • Pharmacology
  • Fibrosis Research

Background:

  • The renin-angiotensin system (RAS) is implicated in liver fibrosis.
  • Intrahepatic RAS components like angiotensin-II (AT-II) activate hepatic stellate cells (Ac-HSC) and increase TGF-beta.
  • AT-II also upregulates tissue inhibitor of metalloproteinases-1 (TIMP-1) via protein kinase-C signaling in Ac-HSC.

Purpose of the Study:

  • To investigate the role of the intrahepatic RAS in liver fibrosis.
  • To evaluate the antifibrotic effects of ACE inhibitors (ACE-I) and AT1-receptor blockers (ARB).
  • To explore combination therapy with interferon (IFN) for liver fibrosis.

Main Methods:

  • Review of studies on intrahepatic RAS activity in liver fibrosis.
  • Assessment of ACE-I and ARB effects on experimental liver fibrosis models.
  • Analysis of clinical data on ARB and combination therapy (IFN + ACE-I) in human liver diseases.

Main Results:

  • ACE-I and ARB attenuated experimental liver fibrosis by suppressing Ac-HSC and TGF-beta.
  • ARB completely suppressed AT-II-induced TIMP-1 upregulation in Ac-HSC.
  • Clinical studies showed ARB improved liver fibrosis scores and TGF-beta in chronic hepatitis C and NASH.
  • Combination therapy with low-dose IFN and ACE-I improved serum fibrosis markers in IFN-refractory chronic hepatitis C.

Conclusions:

  • The interaction between AT-II and AT1-R is crucial in liver fibrosis development.
  • ACE-I and ARB are effective antifibrotic agents with a good safety profile.
  • Combination therapy with ACE-I/ARB and IFN represents a potential novel strategy for liver fibrosis treatment.

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