Angiotensin-(1–7): beyond the cardio-renal actions

It is well known that the RAS (renin–angiotensin system) plays a key role in the modulation of many functions in the body. AngII (angiotensin II) acting on AT1R (type 1 AngII receptor) has a central role in mediating most of the actions of the RAS. However, over the past 10 years, several studies have presented evidence for the existence of a new arm of the RAS, namely the ACE (angiotensin-converting enzyme) 2/Ang-(1–7) [angiotensin-(1–7)]/Mas axis. Ang-(1–7) can be produced from AngI or AngII via endo- or carboxy-peptidases respectively. ACE2 appears to play a central role in Ang-(1–7) formation. As described for AngII, Ang-(1–7) also has a broad range of effects in different organs and tissues which goes beyond its initially described cardiovascular and renal actions. Those effects are mediated by Mas and can counter-regulate most of the deleterious effects of AngII. The interaction Ang-(1–7)/Mas regulates different signalling pathways, such as PI3K (phosphoinositide 3-kinase)/AKT and ERK (extracellularsignal-regulated kinase) pathways and involves downstream effectors such as NO, FOXO1 (forkhead box O1) and COX-2 (cyclo-oxygenase-2). Through these mechanisms, Ang-(1–7) is able to improve pathological conditions including fibrosis and inflammation in organs such as lungs, liver and kidney. In addition, this heptapeptide has positive effects on metabolism, increasing the glucose uptake and lipolysis while decreasing insulin resistance and dyslipidaemia. Ang-(1–7) is also able to improve cerebroprotection against ischaemic stroke, besides its effects on learning and memory. The reproductive system can also be affected by Ang-(1–7) treatment, with enhanced ovulation, spermatogenesis and sexual steroids synthesis. Finally, Ang-(1–7) is considered a potential anti-cancer treatment since it is able to inhibit cell proliferation and angiogenesis. Thus the ACE2/Ang-(1–7)/Mas pathway seems to be involved in many physiological and pathophysiological processes in several systems and organs especially by opposing the detrimental effects of inappropriate overactivation of the ACE/AngII/AT1R axis.