Differential regulation of TGF-β signal in hepatic stellate cells between acute and chronic rat liver injury

Tahashi, Yoshiya; Matsuzaki, Koichi; Date, Masataka; Yoshida, Katsunori; Furukawa, Fukiko; Sugano, Yasushi; Matsushita, Makoto; Hirono, Yasuo; Inagaki, Yutaka; Inoue, Katsumi

doi:10.1053/jhep.2002.30083

Cited by 171 publications

(130 citation statements)

References 34 publications

(49 reference statements)

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“…For example, tumor necrosis factor-α (TNF-α)-induced abrogation of TGF-β-dependent profibrotic responses was linked to the induction of endogenous Smad7 (20). On the other hand, defective Smad7 induction is implicated in the exaggerated TGF-β responsiveness characteristic of hepatic cells and myofibroblasts from chronically injured livers (21,22). In the present study, we observed that the expression of Smad7 began to increase after TGF-β treatment for 4 h. These data agree well with previous results obtained for skin fibroblasts (23).…”

Section: Discussionsupporting

confidence: 93%

Mechanism of the transforming growth factor-β induction of fibronectin expression in hepatic stem-like cells

Cui

Jin

2010

Braz J Med Biol Res

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Section: Discussionsupporting

confidence: 93%

Mechanism of the transforming growth factor-β induction of fibronectin expression in hepatic stem-like cells

Cui

Jin

2010

Braz J Med Biol Res

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“…TGF-b has been shown to be a key profibrogenic cytokine, as it has a prominent role in the production of extracellular matrix by activated HSC. 29 In particular, TGF-b1, which is a well-studied mediator in hepatic fibrogenesis, promotes HSC transition into the myofibroblast 29 and is involved in the formation of a-SMA fiber formation in the myofibroblast. 30 The major cellular mechanisms of CCl 4 are suggested to produce free radicals, which damage the hepatocyte by causing lipid peroxidation and binding cell structures.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori promotes hepatic fibrosis in the animal model

Goo

Lee

et al. 2009

Laboratory Investigation

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Helicobacter pylori infection has been reported to be very common in patients with chronic liver diseases, including cirrhosis. To elucidate the pathological effect of H. pylori infection on the progression of hepatic fibrosis, C57BL/6 mice and Sprague-Dawley rats were orally inoculated with H. pylori, and hepatic fibrosis was induced with carbon tetrachloride (CCl 4 ) administration. We observed the histopathological changes and the presence of H. pylori genes by PCR in the liver. Significant increase in the fibrotic score as well as in serum alanine aminotransferase and aspartate aminotransferase levels was shown in the CCl 4 þ H. pylori group compared with that in the CCl 4 -treated group. Compared with the CCl 4 -treated group, a-smooth muscle actin and transforming growth factor-b1 were enhanced; however, senescence marker protein-30, a multifunctional protein protecting hepatocytes against oxidative stress and apoptosis, was suppressed in the CCl 4 þ H. pylori group. The 16S rRNA (400 bp) was demonstrated by PCR for H. pylori genes from genomic DNA extracted from the liver, and H. pylori-infected mice showed 93.8% (15 of 16) seropositivity by contrast with seronegativity in all H. pylori-noninfected mice. In addition, immunohistochemical study against H. pylori showed positive antigen fragments in the liver of the infected groups. Consequently, our data suggest that H. pylori infection could be an important contributing infectious factor to the development of liver cirrhosis.

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“…Aberrant regulation of Smad7 activity could be implicated in the development of human diseases, such as inflammatory bowel diseases and scleroderma, in which inappropriate expression of TGF-␤ has been shown to play, at least in part, a causative role (5,6). In chronic rat liver injury, the constitutive phosphorylation of Smad2 under a low level of Smad7 could be involved in the progression of liver fibrosis, whereas a transient induction of Smad7 terminated Smad2 phosphorylation in acute liver injury (19). However, controversy concerning the levels of Smad7 in kidney diseases remains; Uchida et al (20) reported a decrease in glomerular expression of Smad7 in anti-Thy-1 nephritis, which is an experimental model of acute reversible mesangial proliferative glomerulonephritis in rats.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice

Fukasawa

Yamamoto

Togawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

193

206

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Overexpression of transforming growth factor ␤ (TGF-␤) has been shown to play pathogenic roles in progression of renal fibrosis, and the severity of tubulointerstitial fibrosis correlates better with renal function than the severity of glomerulosclerosis. Smad proteins are signaling transducers downstream from TGF-␤ receptors. Three families of Smad proteins have been identified: receptorregulated Smad2 and Smad3, common partner Smad4, and inhibitory Smad7 (part of a negative-feedback loop). We investigated Smad-mediated TGF-␤ signaling pathway and regulatory mechanisms of inhibitory Smad7 in unilateral ureteral obstruction (UUO) kidneys in mice, a model of progressive tubulointerstitial fibrosis. Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased. Furthermore, we demonstrated that both the degradation and ubiquitination activity of Smad7 protein were increased markedly in UUO kidneys compared with sham-operated ones. We also found that both Smurf1 and Smurf2 (Smad ubiquitination regulatory factors), which are E3 ubiquitin ligases for Smad7, were increased and that they interacted with Smad7 in UUO kidneys. Our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis.transforming growth factor ␤ ͉ Smad proteins ͉ tubulointerstitial fibrosis

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Differential regulation of TGF-β signal in hepatic stellate cells between acute and chronic rat liver injury

Cited by 171 publications

References 34 publications

Mechanism of the transforming growth factor-β induction of fibronectin expression in hepatic stem-like cells

Mechanism of the transforming growth factor-β induction of fibronectin expression in hepatic stem-like cells

Helicobacter pylori promotes hepatic fibrosis in the animal model

Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice

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