Effects of perindopril and valsartan on expression of transforming growth factor-beta-Smads in experimental hepatic fibrosis in rats.
BACKGROUND
Previous studies have shown that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of hepatic fibrosis, and blockers of the RAS may be active as an antifibrogenic goal. However, the potential role of RAS inhibition on expression transforming growth factor (TGF)-beta-Smads in hepatic fibrosis remains unknown. The aim of this study was to investigate the effect and mechanism of an angiotensin-converting enzyme inhibitor (perindopril) and an angiotensin II receptor blocker (valsartan) on TGF-beta1 and TGF receptor II (TRII) mRNA, Smad3 and Smad7 in fibrotic hepatic livers in rats.


METHODS
Sixty Wistar rats were randomly divided into four study groups (n = 15 for each group), including normal controls, hepatic fibrosis models, and two treated groups with either perindopril or valsartan, starting from the fourth week after being exposed to carbon tetrachloride (CCl(4)) for 4 weeks. The levels of TGF-beta and TRII mRNA in liver tissue were analyzed by RT-PCR. The expressions of TGF-beta1, Smad3 and Smad7 in liver tissues were evaluated by immunohistochemistry. The liver histopathology was examined by hematoxylin and eosin (HE) staining and by electron microscopy, respectively. The liver function and serum hyaluronic acid were also assayed by biochemistry and radioimmunoassay.


RESULTS
Compared with the hepatic fibrosis models, the levels of TGF-beta1, TRII mRNA and the expression Smad3 significantly decreased in the two treated groups, and the expression of Smad7 was significantly increased in the liver of rats treated with perindopril or valsartan (P < 0.05 or P < 0.01). The histological changes and ultrastructure of fibrotic liver, liver function and hyaluronic acid also remarkably improved in the treated rats.


CONCLUSIONS
The angiotensin-converting enzyme inhibitors perindopril and valsartan have a protective effect on liver injury and can ameliorate hepatic fibrosis in rats induced by CCl(4). The mechanisms may be associated with their effects of down-regulating TGF-beta1, TRII mRNA and smad3, and up-regulating Smad7.
Xu
Wei
W
Department of Infectious Diseases, Renmin Hospital, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
Song
Shiling
S
Huang
Yanqing
Y
Gong
Zuojiong
Z
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015870:Gene Expression; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020913:Perindopril / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D051906:Smad7 Protein / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D000959:Antihypertensive Agents; D012333:RNA, Messenger; D051900:Smad3 Protein; D051906:Smad7 Protein; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D000068756:Valsartan; D014633:Valine; D020913:Perindopril