Tankyrase(TNKS) inhibiting autophagy promotes the TGF-ß induced EMT process in vitro and Bleomycin(BLM) induced pulmonary fibrosis in rats

Abstract

Background: IPF is a serious disease. It’s believed the EMT process plays a crucial role in the pathogenesis of IPF, but the mechanism for regulating EMT isn’t fully clear. Therefore, we explored a new mechanism for regulating EMT processes, which may provide ideas for future drug development. In our previous study, we have found that in the BLM-induced rhesus pulmonary fibrosis model, the content of TNKS is significantly correlated with the severity of the disease, while autophagy in the model group showed a significant down-regulation relative to the normal group. Aim: The study tries to reveal the mechanism between TNKS, autophagy and EMT process. Methods: We used TGF-β to stimulate EMT in rat alveolar type II cells (AT II), and BLM was used to induce rats pulmonary fibrosis. The activation of TNKS was inhibited by XAV-939. 3-ma and Rapamycin were used to regulate autophagy levels in vivo and vitro. The activation of autophagy was determined by Beclin1 and the ratio of LC3B II/I. The level of EMT was determined by the levels of E-cad and α-SMA. Results: Under the stimulation of TGF-β or BLM, the content of TNKS in ATII cells and rat lung increased significantly, and autophagy activation was inhibited. After inhibiting the activity of TNKS, the level of autophagy increased, while the activation of EMT decreased, and the Masson staining showed a reduction in the degree of fibrosis. Regulation of autophagy can affect EMT and pulmonary fibrosis, but does not affect the levels of TNKS. Conclusions: This study demonstrated that TNKS affect the progression of EMT by regulating autophagy. Inhibition of TNKS activity may be a new treatment of IPF