Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison

Abstract

The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1-7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning.

Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats

“…AT 2 R-AT 1 R heterodimerization may also affect intracellular AT 1 R signalling [44,45] resulting in a functional inhibition of the latter and adding to the complexity of AT 2 R physiopathology. Nevertheless, as AT 2 R antagonists like PD123319 have also been reported to also antagonize Mas receptor mediated effects [46], other effects not directly linked to AT 2 R stimulation, or an interaction with the Mas-related G-protein-coupled receptor cannot be entirely excluded. However, we also showed that co-infusion of L-NAME abolished the improvement in baroreceptor sensitivity induced by central AT 2 R stimulation by C21, indicating that these effects of AT 2 R stimulation require a functional central NO pathway.…”

Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

“…Functional inter-dependence observed in our study is in agreement with other studies showing abilities of AT 2 R antagonist to prevent the effects involving MasR and vice versa. 20–27,29,38,39 However, these in vivo and in vitro studies in isolated proximal tubule provide an interesting observation in that agonist activation of one receptor may not be critical for another receptor to function. This notion is supported by in vitro studies in isolated proximal tubules where either of the agonists alone AT 2 R agonist C21 or MasR agonist Ang-(1-7) was sufficient to increase NO formation.…”

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…An interesting study even suggests that like ANG II, alamandine acts on both AT 1 and AT 2 receptors to cause both vasopressor and vasodepressor effects in 2K1C hypertensive rats [223]. Taken together, the findings that the AT 2 receptor antagonist PD123319 completely displaced alamandine receptor binding and blocked alamandine-induced aortic vasorelaxation, and that the Mas antagonist A-779 had no effect in blocking alamandine binding, raise more questions than answers on whether alamandine is a truly endogenous or physiological agonist for the alamandine/MrgD axis or the ANG II/ANG III/AT 2 receptor/cGMP axis [48,49,224]. More studies are required to confirm the structure, biochemistry, the physiological role and therapeutic implications of alamandine in cardiovascular, hypertensive and kidney diseases.…”