Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

Sato, Yasunori; Harada, Kenichi; Furubo, Shinichi; Kizawa, Kazuo; Sanzen, Takahiro; Yasoshima, Mitsue; Ozaki, Satoru; Isse, Kumiko; Sasaki, Motoko; Nakanuma, Yasuni

doi:10.2353/ajpath.2006.051136

Cited by 26 publications

(24 citation statements)

References 49 publications

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“…Similarly, an epidermal growth factor tyrosine kinase inhibitor (gefitinib) significantly has been shown to reduce cystic bile duct dilatation of the PCK rat in vivo, but kidney lesions were unaffected or rather worsened according to our previous study [34]. These results suggest that the mechanism of cyst progression of the PCK rat may be different between the liver and kidney.…”

Section: Discussionsupporting

confidence: 69%

Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat

et al. 2014

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The polycystic kidney (PCK) rat is an animal model of Caroli’s disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte proliferation of the PCK rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell proliferative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell proliferative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell proliferative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat, and inhibition of the pathway can reduce cholangiocyte proliferation via the mechanism involving apoptosis and/or autophagy.

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Section: Discussionsupporting

confidence: 69%

Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat

et al. 2014

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“…Hyper-proliferation of cholangiocytes associated with cell cycle dysregulation are considered to be major contributing mechanisms in hepatic cyst growth. 37,45 Indeed, substantial evidence demonstrates that an increased rate of cholangiocyte proliferation is triggered by activation of the EGF-stimulated mitogen-activated protein kinase (MAPK) pathway, 46 upregulation of the cAMP signaling, 45 downregulation of the calcium signaling, 45,47 and deregulation of the cell cycle 38 (Fig. 3).…”

Section: Molecular Pathways In Cholangiociliopathies and Mirnamentioning

confidence: 99%

MicroRNAs in cholangiociliopathies

Masyuk

LaRusso³

2009

Cell Cycle

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This review is focused on current findings implicating miRNAs in the polycystic liver diseases, which we categorized as cholangiociliopathies. Our recent data suggest that deregulation of miRNA pathways is emerging as a novel mechanism in the development of cholangiociliopathies. Experimental evidence demonstrates that miRNAs (i.e., miR-15a) influence hepatic cyst growth by affecting the expression of the cell cycle regulator, Cdc25A. Given that abnormalities in many cellular processes (i.e., cell cycle regulation, cell proliferation, cAMP and calcium signaling, the EGF-stimulated mitogen-activated protein kinase (MAPK) pathway and fluid secretion) contribute to the hepatic cystogenesis, the potential role of miRNAs in regulation of these processes is discussed.

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“…20 Transforming growth factor (TGF)-␤ is known to be the most potent inducer of EMT, and it initiates morphological transition of the cells from an epithelial to a fibroblastic appearance, accompanied by a loss of epithelial cell markers such as Ecadherin and a gain of mesenchymal cell markers such as vimentin, fibronectin, and N-cadherin. 18,19 According to our previous study, 14 administration of a tyrosine kinase inhibitor inhibited intrahepatic bile duct dilation of the PCK rat, and this inhibition resulted in an improvement of hepatic fibrosis. In a rat model of biliary fibrosis, bile duct epithelial cells participate in the fibrotic process by producing connective tissue growth factor.…”

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confidence: 94%

“…With regard to the mechanism of progressive dilation of intrahepatic bile ducts, our pervious studies have shown that activation of the signaling pathway mediated by epidermal growth factor receptor is involved in the abnormal cholangiocyte growth in the PCK rat. 13,14 In most types of chronic liver diseases, activated hepatic stellate cells/myofibroblasts play major roles in hepatic fibrosis by producing extracellular matrix molecules. 15 These fibrogenic processes usually occur after hepatocellular damage by various causative agents, whereas lack of necroinflammatory change in hepatic parenchyma is a histological feature of Caroli's disease with CHF.…”

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Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

Sato

Harada

Ozaki

et al. 2007

The American Journal of Pathology

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The polycystic kidney (PCK) rat is an animal model of Caroli's disease with congenital hepatic fibrosis, in which the mechanism of progressive hepatic fibrosis remains unknown. This study aimed to clarify the mechanism of hepatic fibrosis of the PCK rat from the viewpoint of the contribution of pathological cholangiocytes. In liver sections of the PCK rats, intrahepatic bile ducts were constituted by two different phenotypes: bile ducts lined by cuboidal-shaped and flat-shaped cholangiocytes. The flat-shaped cholangiocytes showed reduced immunohistochemical expression of the biliary epithelial marker cytokeratin 19 and positive immunoreactivity for vimentin and fibronectin. When cultured cholangiocytes of the PCK rat were treated with transforming growth factor (TGF)-␤1, a potent inducer of epithelial-mesenchymal transition, induction of vimentin, fibronectin, and collagen expression occurred in the PCK cholangiocytes. Although the TGF-␤1 treatment reduced cytokeratin 19 expression, the epithelial cell features characterized by the expression of E-cadherin and zonula occludens-1 was maintained, and ␣-smooth muscle actin expression was not induced in the cholangiocytes. Cholangiocytes of the PCK rat may acquire mesenchymal features in response to TGF-␤1 and participate in progressive hepatic fibrosis by producing extracellular matrix molecules, which seems to be a different event from epithelial-mesenchymal transition.

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Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

Cited by 26 publications

References 49 publications

Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat

Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat

MicroRNAs in cholangiociliopathies

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

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