title: Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development.
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 CCl(4)- 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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, 634-8522, Nara, Japan
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: Hiroo
authors.initials: H
authors.lastname: Imazu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui