ACE2 and ANG (1-7) reduce pulmonary injury
An extensive literature has emerged describing the protective effects of ACE2 and ANG (1-7) in mitigating pulmonary injury by acting in opposition to the effects of ANG II. The approaches include treatment with soluble ACE2 that ultimately converts ANG II to ANG (1-7), whose protective role is most likely mediated by MAS1.
Data from rodent models indicate that ACE2/ANG (1-7) can mitigate fibrosis induced by agents such as bleomycin. For example, in a mouse bleomycin model, treatment with recombinant ACE2 reduced epithelial injury, pro-fibrotic cytokine release, activation of fibroblasts and inflammatory cell infiltration, thereby prominently reducing the extent of lung injury (Wang et al., 2015). Studies in a bleomycin model in rats have revealed that the protective effects by ANG (1-7) may occur by inhibition of signaling cascades that involve MAP Kinase and NFkB (Meng et al., 2014). The authors also found the ANG (1-7) or ACE2 overexpression had antifibrotic effects via inhibition of MAP Kinase and NFkB in human lung fibroblasts. Other studies confirm a protective role by ACE2/ANG (1-7) in bleomycin-treated rats (Wu et al., 2014). Lung samples from patients with idiopathic pulmonary fibrosis (IPF) or from bleomycin-treated mice and rats have decreased ACE2 expression in association with lung injury and fibrosis (Li et al., 2007). Fibrosis (collagen accumulation) was also enhanced in mice treated with ACE2 siRNA or ACE2 inhibition but treatment with recombinant ACE2 reduced bleomycin-induced fibrosis (Li et al., 2008b). In a cigarette smoke-induced model of lung injury in mice, Zhang et al., (2018) showed that treatment with ANG 1-7 reduced lung inflammation and fibrosis.
ACE2/ANG (1-7) also have a protective effect in ALI/ARDS models induced by LPS stimulation. In LPS-induced ARDS models in rats, treatment with ANG (1-7) or an ARB reduced lung injury and inflammation and improved lung function (Wösten‐van Asperen et al., 2011; (Chen et al., (2013). He et al., (2015) reported that mesenchymal stem cells (MSCs) engineered to overexpress ACE2 had strong protective effects in an ALI model, improving endothelial barrier integrity and reducing lung injury and inflammation. Inhibition of ACE2 increased lung injury, IL-17 signaling and inflammation with infiltration by neutrophils in a murine model of bacterial (Pseudomonas) lung infection but the converse occurred in mice treated with recombinant ACE2 (Sodhi et al., 2019). ACE2 not only mitigated lung injury but also improved response to the infection. Ex-vivo experiments with mouse lung organoids confirmed the effects of ACE2 limiting IL-17 signaling.
In-vitro data with human cells support the idea that ACE2/ANG (1-7) can protect cells from ANG II or bleomycin-induced apoptosis. It has been suggested that endoplasmic-reticulum (ER) stress induces apoptosis, which can be eliminated by treatment with ANG (1-7) via MAS1 receptor activation (Uhal et al., 2011; Uhal et al., 2013). TGF-β1 treatment promotes EMT in human airway epithelial cells, a response associated with a reduction of ACE2 expression and elevation of migration and expression of myofibroblast markers; treatment with ANG (1-7) blocked TGF-β1-induced EMT and activation of targets downstream of TGF-β1 (Shao et al., 2019).
Effects of the MAS1 receptor in modulating immune response have been reported in a number of studies. These include effects of MAS1 on neutrophil influx in models of arthritis in mice and rats (Silveira et al., 2010) and on the ability of macrophages to phagocytose neutrophils that have undergone apoptosis (Barroso et al., 2017). MAS1 knockout mice have greater inflammatory cell infiltration, lung remodeling and inflammatory cytokine production in models of allergic pulmonary inflammation (Magalhães et al., 2016) and altered macrophage function that contributes to a range of inflammatory pathology (Hammer et al., 2016).
Thus, considerable data document a protective role for ACE2/ANG (1-7) by opposing effects of ANG II in lung injury. ACE2/ANG (1-7) have many such actions, which include blunting of alveolar epithelial apoptosis, infiltration of inflammatory cells, activation of fibroblasts and endothelial disruption.