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.