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- Title
Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development
- Authors
Yoshiji, Hitoshi; Kuriyama, Shigeki; Yoshii, Junichi; Ikenaka, Yasuhide; Noguchi, Ryuichi; Yanase, Koji; Namisaki, Tadashi; Yamazaki, Masaharu; Tsujinoue, Hirohisa; Imazu, Hiroo; Fukui, Hiroshi
- Abstract
It has been shown that tissue inhibitor of metalloproteinases-1 (TIMP-1) plays an important role in the progression of liver fibrosis. TIMP-1 gene expression is regulated by several factors in vivo. Among them, angiotensin-II (AT-II) induces TIMP-1 in endothelial cells (EC) in vitro, however, the interaction between these molecules in liver fibrogenesis has not yet been elucidated. The aim of this study was to examine a possible association between TIMP-1 and AT-II both in vitro and in vivo using the clinically available angiotensin-I converting enzyme (ACE) inhibitor, perindopril (PE), and the AT-II type 1 receptor blocker (ARB), candesartan (CA). In cultured activated hepatic stellate cells (HSC), AT-II increased TIMP-1 in a dose- and time-dependent manner. CA and LY 333531, the protein kinase C (PKC) inhibitor, blocked this augmentation in a dose-dependent manner. In the CCl4- and pig serum-induced rat liver fibrosis model, a clinically comparable low dose of PE and CA significantly suppressed liver fibrosis development associated with the suppression of TIMP-1 expression in the liver. AT-II induces TIMP-1 via type 1 receptor and PKC as an intracellular signaling pathway in activated HSC. These results suggested that the AT-II-induced TIMP-1 plays an important role in liver fibrosis development.
- Subjects
METALLOPROTEINASES; LIVER diseases; GENE expression; ACE inhibitors; PROTEIN kinases
- Publication
Hepatology Research, 2003, Vol 27, Issue 1, p51
- ISSN
1386-6346
- Publication type
Article
- DOI
10.1016/S1386-6346(03)00160-8