Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
Notch signaling is essential to the regulation of cell differentiation, and aberrant activation of this pathway is implicated in human fibrotic diseases, such as pulmonary, renal, and peritoneal fibrosis. However, the role of Notch signaling in hepatic fibrosis has not been fully investigated. In the present study, we show Notch signaling to be highly activated in a rat model of liver fibrosis induced by carbon tetrachloride (CCl(4)), as indicated by increased expression of Jagged1, Notch3, and Hes1. Blocking Notch signaling activation by a γ-secretase inhibitor, DAPT, significantly attenuated liver fibrosis and decreased the expression of snail, vimentin, and TGF-β1 in association with the enhanced expression of E-cadherin. The study in vitro revealed that DAPT treatment could suppress the EMT process of rat hepatic stellate cell line (HSC-T6). Interestingly, DAPT treatment was found not to affect hepatocyte proliferation in vivo. In contrast, DAPT can inhibit hepatocyte apoptosis to some degree. Our study provides the first evidence that Notch signaling is implicated in hepatic fibrogenesis and DAPT treatment has a protective effect on hepatocytes and ameliorates liver fibrosis. These findings suggest that the inhibition of Notch signaling might present a novel therapeutic approach for hepatic fibrosis.
Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, People's Republic of China.
Yixiong
Y
Chen
Shaoping
S
Zheng
Dan
D
Qi
Shaojiang
S
Zheng
Junli
J
Guo
Shuling
S
Zhang
Zhihong
Z
Weng
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000517:prevention & control*; D034741:RNA, Small Interfering; D051381:Rats; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases