Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats

J Hepatol. 2002 Jul;37(1):22-30. doi: 10.1016/s0168-8278(02)00104-6.


Background/aims: It is suggested that the renin-angiotensin system (RAS) is involved in tumor development and fibrogenesis. The aim of the present study was to examine the effect of RAS inhibition on the liver enzyme-altered preneoplastic lesions and fibrosis development.

Methods: The effects of the clinically used angiotensin-I converting enzyme inhibitor (ACE-I), perindopril (PE), on two different rat model of liver carcinogenesis models induced separately by diethylnitrosamine (DEN) and a choline-deficient L-amino acid-defined (CDAA) diet were studied. This CDAA model was also used to elucidate the effect of PE on liver fibrosis development.

Results: The immunohistochemical evaluation revealed that the glutathione S-transferase placental form (GST-P), and gamma-glutamyltransferase (GGT)-positive preneoplastic foci significantly decreased in the livers of the PE-treated groups. In CDAA-induced liver fibrosis model, PE revealed a marked inhibitory effect of liver fibrosis development. The hepatic hydroxyproline, serum fibrosis markers, alpha-smooth muscle actin (alpha-SMA) immunopositive cells in number, and alpha-(III) pro-collagen mRNA expression were significantly suppressed by PE treatment. These inhibitory effects of PE were achieved even at a clinically comparable dose (2 mg/kg per day).

Conclusions: These results suggested that the RAS is involved in liver carcinogenesis and fibrosis development.

MeSH terms

  • Alkylating Agents
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Choline / pharmacology
  • Diethylnitrosamine
  • Disease Models, Animal
  • Liver / enzymology*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / prevention & control
  • Male
  • Perindopril / pharmacology
  • Precancerous Conditions / chemically induced
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / prevention & control
  • Rats
  • Rats, Inbred F344
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology*


  • Alkylating Agents
  • Angiotensin-Converting Enzyme Inhibitors
  • Diethylnitrosamine
  • Choline
  • Perindopril