The renin-angiotensin-system (RAS) is one of the oldest known hormonal systems preserved in multiple species over millions of years. A key enzyme of the system, renin, was discovered in 1898, and ever since a huge body of research has continuously revealed physiological and pathophysiological features of the RAS. Classically, these include, via the so-called angiotensin AT1 receptor, powerful vasoconstriction, regulation of the body fluid balance by inducing thirst, stimulation of aldosterone release from the adrenal cortex, renal salt retention, stimulation of the sympathetic nervous system and, more recently discovered, pro-fibrotic and pro-inflammatory effects. Pathophysiological actions of the RAS, with its extension to those of aldosterone (RAAS), include the induction of arterial hypertension, cardiac and vascular hypertrophy, lung and renal fibrosis, vascular atherosclerosis, perivascular fibrosis or chronic inflammation and others.
Attempts to inhibit the RAS in hypertension and other cardiovascular diseases first led to the clinical introduction of ACE-inhibitors some forty years ago, followed by selective antagonists of the AT1 receptor, the sartans. After a multitude of evidence-generating trials and global success in clinical practice, both approaches are now firmly established in the therapy of hypertension as well as cardio-metabolic and renal diseases. More recently, research has focused on the so-called protective arm of the RAS, mediated by stimulation of the angiotensin AT2 receptor by or by the Mas receptor stimulated by the angiotensin 1–7 peptide. Activation of these systems has exhibited beneficial effects in numerous preclinical studies via opposing AT1-mediated actions and beyond. Other degradation peptides of the angiotensin precursor, angiotensinogen, may also exhibit protective effects via these receptors. Agonists for the AT2 receptor as well as for the ACE2-Mas system have been developed and are currently under clinical evaluation.
It remains to be seen whether the pharmacological stimulation of the protective arm of the RAS will become an effective clinical tool in various cardiovascular and metabolic indications. Theoretically, it would make sense not only to block the harmful RAS but, at the same time, also stimulate the beneficial actions of the system.