Fig. 1. Overview of the renin–angiotensin system.

a | The renin–angiotensin system (RAS) is initiated by renin, which is secreted by the juxtaglomerular cells of the afferent renal arterioles in response to decreased perfusion, in response to low sodium levels, upon β₁-adrenergic receptor stimulation or upon stimulation by nitric oxide (NO) or prostaglandin^259,260. The renin precursor prorenin and renin both bind to prorenin receptor (PRR)²⁶¹. In the circulation, renin cleaves angiotensinogen into angiotensin I (Ang I). Prorenin can also cleave angiotensinogen into Ang I, to a certain extent, when bound to PRR. Ang I can also be generated through the cleavage of Ang 1–12 by angiotensin-converting enzyme (ACE)²⁴⁰ or by chymase in cardiac tissue²⁶². The ensuing proteolytic cascade can be divided into the canonical and non-canonical pathways. The canonical pathway is initiated when ACE, or chymase in the heart, cleaves Ang I into Ang II. Binding of Ang II or its cleavage products Ang III or Ang A to the G-protein-coupled receptor Ang II receptor type 1 (AT1R) leads to vasoconstriction, an increase in blood pressure and other effects^4,221. The non-canonical pathway is initiated by Ang I cleavage by ACE2 to Ang 1–9, which is further cleaved into Ang 1–7 (mainly by ACE). In the non-canonical pathway, binding of Ang II, Ang III, Ang 1–9, Ang 1–7 and Ang A to AT2R counteracts effects mediated by AT1R. Ang IV (generated from Ang III when cleaved by aminopeptidase N (APN)) is involved in both the canonical pathway and the non-canonical pathway and binds to angiotensin 4 receptor (AT4R), also known as insulin-regulated aminopeptidase (IRAP). Binding of Ang IV to AT4R has antiapoptotic and both pro-inflammatory and anti-inflammatory effects, as it regulates responses by competitive inhibition of the enzyme/receptor^218,263,264. Ang 1–7 binds to the receptors MAS and MAS-related G-protein-coupled receptor (MRGD), and alamandine, which is generated from Ang A or Ang 1–7, also binds to MRGD. Both Ang 1–7 and alamandine have antihypertensive, anti-inflammatory and antifibrotic effects²⁶⁵. The non-canonical and canonical RAS pathways can counterbalance each other^{218,263–265}. For example, Ang II binds to both AT2R (non-canonical pathway) and AT1R (canonical pathway) but exerts a more robust effect on AT1R^99,266. AT2R can, however, be upregulated during pathological conditions⁹⁹. Effectors are depicted in circles and the enzymes catalysing their cleavage are listed next to blue arrows. Effectors that predominantly participate in the canonical pathway are coloured pink and those that predominantly participate in the non-canonical pathway are coloured blue. Effectors that participate in both pathways are coloured in both pink and blue, with the predominant colour indicating the more prominent pathway. Black arrows indicate which molecule binds to which receptor, with dashed lines depicting weak receptor binding. b | Amino acid sequences of angiotensin peptides. The cleavage sites of ACE and renin are indicated by blue arrows. AD, aspartate decarboxylase; ADH, antidiuretic hormone; APA, aminopeptidase A; NEP, neprilysin; PEP, prolylendopeptidase; PRCP, prolylcarboxypeptidase; THOP, thimet oligopeptidase.