Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats.
OBJECTIVE
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Tsujinoue
Hirohisa
H
Nakatani
Toshiya
T
Imazu
Hiroo
H
Yanase
Koji
K
Kuriyama
Shigeki
S
Fukui
Hiroshi
H
D000477:Alkylating Agents; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002794:Choline / Q000494:pharmacology; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D008099:Liver / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D020913:Perindopril / Q000494:pharmacology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
D000477:Alkylating Agents; D000806:Angiotensin-Converting Enzyme Inhibitors; D004052:Diethylnitrosamine; D002794:Choline; D020913:Perindopril