Clinical significance of intervention in the renin-angiotensin-aldosterone-apelinergic system

The renin-angiotensin-aldosterone-apelinergic system (RAAAS) offers important targets for highly effective therapies in multiple diseases. RAAAS is comprised of important G-protein coupled receptors (GPCRs) such as MAS receptor, MAS-related GPCR member D (MrgD), angiotensin II type 2 (AT₂) receptor, angiotensin II type 1 (AT₁) receptor and apelin receptor: angiotensin II protein J (APJ). Within RAAAS, further characterization of direct target binding of various frequently used compounds, including presumed MAS receptor antagonists and APJ peptide-antagonists, is urgently needed. D-Pro7-angiotensin-(1-7), a presumed antagonist of MAS receptor and of MrgD, and D-Ala7-Ang-(1-7) bind to AT₂ receptor. This indicates that D-Ala7-Ang-(1-7)- and D-Pro7-angiotensin-(1-7)-dependent effects ascribed to stimulating MAS receptor/MrgD may have resulted from stimulation of AT₂ receptor. As a consequence presumed MAS and MrgD agonists may be AT₂ receptor agonists. APJ has 54 % homology with AT₁ receptor, but angiotensin II does not bind to APJ. However, APJ can form heterodimers with AT₁ receptor, has significant signaling interplay with it and can cause effects that are opposed to AT₁ receptor stimulation, including vasodilation. The combination of these APJ features constitutes an important ground to discern and discuss the renin-angiotensin-aldosterone-apelinergic system, RAAAS, and its therapeutic potential. We here discuss the (potential) clinical impact of intervention in RAAAS with receptor antagonists and enzyme inhibitors, and combination therapies. An outlook for future interventions, including combination therapies with agonists, is provided.