The AT(1)/AT(2) Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System

The AT(1) receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT(2) receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT(1) receptor. The discovery of a local RAS has highlighted the importance of the balance between AT(1)/AT(2) receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT(1) receptor, homo- and heterodimerization, and the use of AT(1) receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT(1)/AT(2) equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT(1) and AT(2) receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives