The Alternative Renin-Angiotensin System: exploration of its therapeutic potential

Abstract

The renin–angiotensin system (RAS) was initially thought to be fairly simple. However, this idea has been challenged following the development of RAS blockers, including renin inhibitors, angiotensin-converting-enzyme (ACE) inhibitors, type 1 angiotensin II (AT1)-receptor blockers and mineralocorticoidreceptor antagonists. Consequently, new RAS components and pathways that might contribute to the effectiveness of these drugs and/or their adverse effects have been identified. For example, an increase in renin levels during RAS blockade might result in harmful effects via stimulation of the prorenin receptor (PRR), and prorenin—the inactive precursor of renin—might gain enzymatic activity on PRR binding. The increase in angiotensin II levels that occurs during AT1-receptor blockade might result in beneficial effects via stimulation of type 2 angiotensin II receptors. Moreover, angiotensin 1–7 levels increase during ACE inhibition and AT1-receptor blockade, resulting in Mas receptor activation and the induction of cardioprotective and renoprotective effects, including stimulation of tissue repair by stem cells. Finally, a role of angiotensin II in sodium and potassium handling in the distal nephron has been identified. This finding is likely to have important implications for understanding the effects of RAS inhibition on whole body sodium and potassium balance.