What is the contribution of AGTR2 to pathobiology in the lung and COVID-19?
Few studies have assessed the actions of AGTR2 in the lung. A protective role for AGTR2 in was implied by findings indicating that AGTR2-null mice and those treated with an AGTR2 inhibitor were more vulnerable to ARDS Imai et al., (2005). However, subsequent studies related to the lungs using selective inhibitors of AGTR2 to distinguish its effects from AGTR1, reach the opposite conclusion: in general, it appears AGTR2 drives pathology synergistically with AGTR1, in particular in cell types relevant to the hypothesis presented above.
Examples of such studies include animal models of fibrosis (Königshoff et al., 2006; Waseda et al., 2008) and in-vitro data from human lung fibroblasts (Königshoff et al., 2006). AGTR2 also promotes apoptosis in pulmonary endothelial cells (Lee et al., 2010), rat alevolar epithelial cells (Bechara et al., 2006) and human alveolar epithelial cell lines (Pickel et al., 2010). Consistent with animal data on fibrosis are histological data from patients with systemic sclerosis and lung fibrosis, showing elevated alveolar AGTR2 expression with disease; higher AGTR2 expression is associated with increased mortality Parra et al., (2014).
Reviews that discuss AGTR2 action in other tissues (e.g., Forrester et al., 2018; Lemarie & Schiffrin, 2010; Jones et al., 2008; Kaschina, & Unger, 2003) also note disagreement regarding AGTR2 action (e.g., effects on vasodilation, protection from ischemic injury), but all concur that AGTR2 exerts pro-apoptotic effects in various cell types. A pro-fibrotic role for AGTR2 that promotes injury in concert with AGTR1 has also been noted in lung fibroblasts Uhal et al., (2012b). We conclude that AGTR2 may act in parallel with AGTR1 in driving cell death and tissue damage in the schema depicted in Figure 3 .