Recent research has found the mRNA of Notch receptors to be present in freshly isolated rat HSCs which displayed no protein synthesis of Notch ligands. 1158279-20-9 However, the amount of Jagged1 protein increased while isolated HSCs developed into myofibroblast-like cells. Based on these studies, we hypothesize that Notch signaling might be involved in liver fibrogenesis. In the present study, we investigated the role of Notch signaling during the process of liver fibrosis and clarified its mechanism. Our results demonstrated that Notch signaling is activated in hepatic fibrosis induced by CCl4 and that blocking Notch signaling using c-secretase inhibitor can significantly attenuate liver fibrosis. These results suggest that selective interruption of Notch signaling might be a novel anti-fibrotic strategy in hepatic fibrosis. In this study, we show that Notch signaling is markedly activated in a rat model of liver fibrosis induced by CCl4. Importantly, treatment with the c-secretase inhibitor DAPT strongly inhibited the activation of HSCs. DAPT treatment also significantly attenuated CCl4-induced hepatic fibrosis in vivo as demonstrated by the decreased ECM accumulation. DAPT treatment was found not to affect hepatocyte proliferation but rather to 572924-54-0 inhibit hepatocyte apoptosis to some degree in vivo. Notch signaling is involved in cell proliferation, survival, apoptosis, and differentiation, all of which affect the development and function of many organs. Recently, Bielesz reported that active Notch signaling pathways in tubular epithelial cells is a critical regulator of tubulointerstitial fibrosis. Another study by Zhu has demonstrated that Notch signaling is highly activated in rats in peritoneal dialysis fluid-induced fibrotic peritoneum. We have previously shown that Notch3 significantly up-regulated in fibrotic liver tissues of patients with hepatitis. The present study reveals that in fibrotic rat liver, the mRNA levels of Notch3, Jagged1, and Hes1 were markedly increased during liver fibrogenesis, and then decreased along with the resolution of fibrosis. This dynamic change was confirmed by western blot analysis. The upregulated expression of Notch3 and Hes1 by activated HSCs and the increased synthesis of Jagged1 by neighboring hepatocytes and activated HSCs itself suggest that Notch signaling is activated in rats with liver fibrosis induced by CCl4. Epithelial-mesenchymal transition is defined as a process whereby epithelial cells gradually lose their epithelial signatures while acquiring the characteristics of mesenchymal cells. Numerous reports have indicated a role for EMT in fibrosis. In particular, recent advances have confirmed that myofibroblasts can be supplemented from cholangiocytes and hepatocytes by EMT during hepatic fibrosis.
