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(American Journal of Pathology. 2005;166:49-60.)
© 2005 American Society for Investigative Pathology

Activation of the MEK5/ERK5 Cascade Is Responsible for Biliary Dysgenesis in a Rat Model of Caroli’s Disease

Yasunori Sato^*, Kenichi Harada^*, Kazuo Kizawa, Takahiro Sanzen, Shinichi Furubo, Mitsue Yasoshima^*, Satoru Ozaki^*, Masahiko Ishibashi and Yasuni Nakanuma^*

From the Department of Human Pathology,^* Kanazawa University Graduate School of Medicine, Kanazawa; the Drug Safety Research Laboratory, Toyama Chemical Company Limited, Toyama; and the College of Environmental Health, Azabu University, Sagamihara, Japan

Polycystic kidney (PCK) rats exhibit a multiorgan cyst pathology similar to human autosomal recessive polycystic kidney disease, and are proposed as an animal model of Caroli’s disease with congenital hepatic fibrosis (CHF). This study investigated the expression and function of selected components of the mitogen activated protein kinase (MAPK) pathway in cultured intrahepatic biliary epithelial cells (BECs) of PCK rats. Compared to the proliferative activity of cultured BECs of control rats, those of the PCK rats were hyperresponsive to epidermal growth factor (EGF). The increase in BEC proliferation was accompanied by overexpression of MAPK/extracellular signal-regulated protein kinase (ERK) kinase 5 (MEK5), and subsequent phosphorylation of ERK5 in vitro. The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA. An EGF receptor tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839), also significantly inhibited the abnormal growth of cultured BECs of PCK rats. By contrast, treatment with PD98059 and U0126, inhibitors for MEK1/2, was less effective. These results suggest that the activation of the MEK5-ERK5 cascade plays a pivotal role in the biliary dysgenesis of PCK rats, and also provide insights into the pathogenesis of Caroli’s disease with CHF. As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy.

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