Exogenous angiotensin (1-7) directly inhibits epithelial-mesenchymal transformation induced by transforming growth factor-β1 in alveolar epithelial cells

• Published in: Biomedicine & pharmacotherapy Vol. 117; p. 109193
• Main Authors: Shao, Min, Wen, Zhi-Bin, Yang, Hui-Hui, Zhang, Chen-Yu, Xiong, Jian-Bing, Guan, Xin-Xin, Zhong, Wen-Jing, Jiang, Hui-Ling, Sun, Chen-Chen, Luo, Xiao-Qin, He, Xiao-Fan, Zhou, Yong, Guan, Cha-Xiang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2019; Elsevier
• Subjects: A549 Cells; Alveolar epithelial cells; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - metabolism; Angiotensin (1-7); Angiotensin converting enzyme 2; Angiotensin I - pharmacology; Animals; Cell Line, Tumor; Epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - drug effects; Humans; Lung - drug effects; Lung - metabolism; Mice; Mice, Inbred C57BL; Peptide Fragments - pharmacology; Phosphorylation - drug effects; Signal Transduction - drug effects; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-β1; Epithelial-mesenchymal transition; Angiotensin (1-7); Transforming growth factor-β1; Angiotensin converting enzyme 2; Alveolar epithelial cells
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109193

•Exogenous Ang-(1-7) directly inhibits EMT induced by TGF-β1 in A549.•TGF-β1 downregulates the ACE2 expression in A549 in a SIRT1-dependent manner.•SIRT1 activator, SRT1720, restores the ACE2 expression in A549. Accumulating evidence indicates that angiotensin (1-7) [Ang-(1-7)] protects against idiopathic pulmonary fibrosis (IPF) in animal experiments. However, whether Ang-(1-7) effectively inhibits epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1) remains unclear. The aim of this study is to examine the eff ;ects of Ang-(1-7) on TGF-β1-induced EMT in human alveolar epithelial cells. We found that angiotensin-converting enzyme 2 (ACE2) /Ang-(1-7)/MasR were decreased in the lungs of mice with IPF induced by bleomycin, and were negatively correlated with Tgfb1 mRNA expression. In vitro, our data showed that exogenous Ang-(1-7) restored the expression of E-cadherin and decreased the expressions of α-SMA and Vimentin induced by TGF-β1 in A549 cells. Ang-(1-7) also reduced TGF-β1-induced migration and synthesis of the extracellular matrix, such as collagen Ⅰ and collagen Ⅲ. Mechanistically, we observed that Ang-(1-7) directly inhibited TGF-β1-induced phosphorylation of Smad2 and Smad3, and suppressed the expression of the downstream target gene of TGF-β1-Smad signaling, including ZEB1, ZEB2, TWIST, and SNAIL1. Additionally, phosphorylation of mTOR induced by TGF-β1 also been suppressed by Ang-(1-7) treatment in A549 cells. Interestingly, we found that TGF-β1 strongly suppressed the expression of ACE2 in A549 cells through inhibiting SIRT1. In conclusion, our findings indicate that Ang-(1-7) directly inhibits TGF-β1-induced EMT in alveolar epithelial cells via disruption of TGF-β1-Smad signaling pathway, contributing to the protective effect against IPF.