The Renin-Angiotensin signaling (RAS) pathway
Figure 2 shows a schema of the RAS pathway and is based on data for angiotensin signaling from a range of sources (Santos, 2014; Zhuo et al., 2013; Tikellis and Thomas, 2012; Karnik et al., 2017, Santos et al., 2019), including the Guide to Pharmacology database (GtoPdb; https://www.guidetopharmacology.org/) (Armstrong et al., 2020). In the “traditional”/canonical RAS pathway, renin is secreted from the kidney and angiotensinogen (AGT) is produced and secreted by the liver. Renin cleaves AGT to form Angiotensin 1 (ANG 1), which in turn generates ANG II or ANG 1-9, primarily from the actions of ACE1 and ACE2, respectively. ANG II is cleaved by multiple enzymes, most importantly ACE2, to form ANG (1-7). ANG II also forms ANG IV via the action of aminopeptidases (APs). Both ANG II and ANG IV act primarily via AGTR1 (a GPCR). ANG (1-7) acts primarily via the MAS1 (a GPCR), and forms ANG (1-5), which signals via MRGPRD (a GPCR). ANG (1-7) can also act via the AGTR2 receptor but with much lower affinity than ANG II (refer GtoPdb entry).
As discussed below, the lung and heart express components of the RAS system, i.e., ‘local’ RAS signaling (e.g., Uhal et al., 2012; Forrester et al., 2018), that can contribute to tissue injury. For example, activated lung fibroblasts and injured epithelial cells express AGT and other RAS components (e.g., Uhal et al., 2012; Wang et al., 2000).
ACE2, a carboxypeptidase (zinc metalloprotease), is the primary enzyme responsible for ANGII degradation, thus regulating signal transduction by ANGII. The conversion by ACE2 of ANG II to ANG (1-7) (and its signaling via MAS1) produces effects that oppose those of ANG II (Karnik et al., 2017, Santos et al., 2018; Santos et al., 2019). ACE2, in particular its catalytic ectodomain, can be shed from cells, an action mediated by the metalloprotease ADAM17, into the circulation as soluble ACE2, levels of which can be increased by Ang II via its ability to increase ADAM17 activity (Lambert et al., 2005; Patel et al., 2014).
The RAS signaling pathway (Figure 2) thus relies on a “yin/yang relationship” between ACE1 and ACE2: ACE1 generates Angiotensin II (ANG II) and in turn, signaling by the GPCRs AGTR1 and AGTR2 while ACE2 generates peptides whose receptors act to oppose responses mediated by AGTR1. AGTR1 is highly expressed and mediates ANGII signaling and effects (including inflammation, apoptosis, pro-fibrotic signaling and tissue remodeling) in pulmonary and cardiac tissue (Forrester et al., 2018). By contrast, the role of AGTR2, which is expressed in the lung and at low levels in the heart, is more controversial (Forrester et al., 2018; Santos et al., 2019; GtoPdb). AGTR2 can mediate effects that oppose those of AGTR1 but other data suggest that AGTR2 promotes effects such as apoptosis. In subsequent section that focus on the pathophysiology of COVID-19, we emphasize the role of ACE1-generated AGTR1 as the key mediator of ANG II actions and the opposing actions of ACE-derived peptides.