AngII (angiotensin II) induces pathological conditions such as fibrosis in skeletal muscle. In this process, AngII increases ROS (reactive oxygen species) and induces a biphasic phosphorylation of p38 MAPK (mitogen-activated protein kinase). In addition, AngII stimulates the expression and production of TGF (transforming growth factor)-β1 via a mechanism dependent on ROS production mediated by NADPH oxidase (NOX) and p38 MAPK activation. In the present study, we investigated whether Ang-(1–7) [angiotensin-(1–7)], through the Mas-1 receptor, can counteract the signalling induced by AngII in mouse skeletal muscle and cause a decrease in the expression and further activity of TGF-β1 in skeletal muscle cells. Our results show that Ang-(1–7) decreased the expression of TGF-β1 induced by AngII in a dose-dependent manner. In addition, we observed that Ang-(1–7) prevented the increase in TGF-β1 expression induced by AngII, ROS production dependent on NOX and the early phase of p38 MAPK phosphorylation. Interestingly, Ang-(1–7) also prevented the late phase of p38 MAPK phosphorylation, Smad-2 phosphorylation and Smad-4 nuclear translocation, an increase in transcriptional activity, as determined using the p3TP-lux reporter, and fibronectin levels, all of which are dependent on the TGF-β1 levels induced by AngII. We also demonstrated that Ang-(1–7) prevented the increase in TGF-β1, fibronectin and collagen content in the diaphragm of mice infused with AngII. All of these effects were reversed by the administration of A779, indicating the participation of Mas-1. In conclusion, our findings support the hypothesis that Ang-(1–7) decreases the expression and further biological activity of TGF-β1 induced by AngII in vitro and in vivo.
The Ang-(1–7)/Mas-1 axis attenuates the expression and signalling of TGF-β1 induced by AngII in mouse skeletal muscle
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María Gabriela Morales, Johanna Ábrigo, Carla Meneses, Felipe Simon, Franco Cisternas, Juan Carlos Rivera, Yaneisi Vazquez, Claudio Cabello-Verrugio; The Ang-(1–7)/Mas-1 axis attenuates the expression and signalling of TGF-β1 induced by AngII in mouse skeletal muscle. Clin Sci (Lond) 1 July 2014; 127 (4): 251–264. doi: https://doi.org/10.1042/CS20130585
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