Renin-angiotensin cascade — renin (with the (pro)renin receptor) cleavage of angiotensinogen, ACE or chymase/cathepsin G formation of angiotensin II, the ACE2/neprilysin/PRCP angiotensin-(1-7) arm acting on MAS1, and the ENPEP/ANPEP aminopeptidase arm to angiotensin III and IV

The renin-angiotensin cascade is the extracellular proteolytic pathway that generates the family of angiotensin peptide hormones from a single precursor, angiotensinogen (AGT), a liver-secreted serpin-fold glycoprotein that does none of the cleaving itself. Renin (REN), an aspartic endopeptidase released by the juxtaglomerular cells of the kidney, cleaves the N-terminal Leu-Val bond of angiotensinogen and releases the inactive decapeptide angiotensin I; this is the rate-limiting step. On tissue surfaces renin and its zymogen prorenin bind the (pro)renin receptor ATP6AP2, which raises renin's catalytic efficiency and lets prorenin act without proteolytic activation. The zinc peptidyl-dipeptidase angiotensin-converting enzyme (ACE), anchored on endothelial cells and also shed into plasma, removes the C-terminal His-Leu dipeptide of angiotensin I to give the octapeptide angiotensin II, the principal effector, which acts on the AT1 and AT2 receptors. In tissues, angiotensin II is also formed independently of ACE by the mast-cell serine protease chymase (CMA1) and by neutrophil cathepsin G (CTSG). A counter-regulatory arm converts the pressor peptides into angiotensin-(1-7): the monocarboxypeptidase ACE2 removes the C-terminal phenylalanine of angiotensin II (its preferred substrate) and the C-terminal leucine of angiotensin I to give angiotensin-(1-9); neprilysin (MME) cleaves angiotensin I and angiotensin-(1-9) to angiotensin-(1-7), as ACE also does for angiotensin-(1-9); and the lysosomal prolylcarboxypeptidase PRCP releases the C-terminal phenylalanine of angiotensin II and III. Angiotensin-(1-7) is the agonist of the G protein-coupled receptor MAS1 and opposes angiotensin II with vasodilator and antiproliferative actions. A third arm trims angiotensin II from the N terminus: glutamyl aminopeptidase (aminopeptidase A, ENPEP) removes Asp1 to give angiotensin III, which still acts on the AT1 and AT2 receptors and dominates in the brain renin-angiotensin system, and alanyl aminopeptidase (aminopeptidase N, ANPEP) removes Arg1 of angiotensin III to give angiotensin IV.

Derived from the RGD Pathway Ontology term PW:0000492 (renin-angiotensin cascade pathway) through the RGD_PATHWAY_ONTOLOGY project (seed in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml), mapped to GO:0002003 angiotensin maturation. PW:0000492 is the only PW evidence source_id: the module covers the proteolytic cascade. The diagram's receptor-signalling sub-pathways (PW:0000244, PW:0000527, PW:0000528 and the angiotensin III branches PW:0000457, PW:0000530, PW:0000531) and the angiotensin IV and angiotensin-(1-7) signalling pathways (PW:0000458, PW:0000529) are mentioned in prose but are not evidence here; the angiotensin II ones are the evidence of modules/angiotensin_ii_receptor_signaling.yaml. (1) BOUNDARY WITH ANGIOTENSIN II RECEPTOR SIGNALLING. This module is the part that modules/angiotensin_ii_receptor_signaling.yaml deliberately left out (its note 1). The receptor step is part 3, a module_ref to that module, and is not re-modelled; the AGT Angiotensin-2 hormone annoton, AGTR1 and AGTR2 live there. Angiotensin III is routed to the same module because it acts on the same two receptors. (2) AGT IS THE SUBSTRATE, NOT A PARTICIPANT (CLAUDE.md worked example, PR #2972). GO:0002003 is_a GO:0016486 peptide hormone processing, so the term names whatever does the cleaving. Angiotensinogen supplies no residue beyond the bond that is cut, positions nothing and catalyses nothing; renin, ACE and the other peptidases perform every step. AGT therefore appears (a) as the substrate (has_input) of every protease annoton, matching the has_input AGT edges on REN and ACE in gomodel:6246724f00000549, and (b) as the hormone source of angiotensin-(1-7) acting on MAS1 in part 5, paralleling the Angiotensin-2 hormone annoton of the receptor module. It carries no GO:0002003 process anywhere in this file. QuickGO (November 2026) confirms human AGT has no GO:0002003 row; its gene review records protease binding and hormone activity as core functions. The substrate peptides are named by AGT residue range in preferred_term (angiotensin I 25-34, angiotensin-(1-9) 25-33, angiotensin II 25-32, angiotensin-(1-7) 25-31, angiotensin III 26-32, angiotensin IV 27-32, the PEPTIDE features of the AGT UniProt entry) and grounded to the AGT accession. (3) THE (PRO)RENIN RECEPTOR. ATP6AP2 is included in the renin step as a cofactor annoton, not as a protease: it binds renin and prorenin, raises renin's catalytic efficiency about fourfold and makes prorenin active without proteolysis (PMID:12045255; Reactome R-HSA-2022403, R-HSA-2065357). Unlike AGT it does contribute to the work of the step, which is why GOA's two IDA rows placing it in GO:0002003 are kept (the ATP6AP2 gene review accepts both) and why the comparator logic of note 2 does not exclude it. Its function here is GO:0016504 peptidase activator activity on renin, the capacity the cascade uses, rather than the GO:0004888 transmembrane signaling receptor activity of its gene review's core function, which is the out-of-scope ERK signalling. GOA has no experimental MF row for it other than bare protein binding, which is not used. Its renin-triggered ERK signalling and its V-ATPase accessory role are outside the module. Whether receptor binding is physiologically important for angiotensin generation in vivo is debated, which is recorded as a knowledge gap. (4) MOLECULAR FUNCTIONS. Chosen from each protein's experimental GOA rows in QuickGO (November 2026): REN GO:0004190 (EXP/IDA PMID:12045255 and older kinetic papers); ACE GO:0008241 (EXP, IDA PMID:11432860, PMID:1320019); ACE2 GO:0004180 (IDA PMID:10924499, PMID:10969042, PMID:15283675; its single IDA GO:0008241 row was not used because on the angiotensins it acts only as a carboxypeptidase; the zinc metallo- child GO:0004181 was considered, but its only human ACE2 row is an IEA transfer from the mouse ortholog, so the IDA-supported parent is kept); MME GO:0004222 (EXP/IDA); CMA1 GO:0004252 (IDA, IBA; EXP rows are to the parent terms endopeptidase and serine-type peptidase activity); CTSG GO:0004252 (EXP/IDA); ENPEP GO:0004230 (EXP PMID:23888046); ANPEP GO:0070006 (IBA; experimental rows only TAS aminopeptidase activity); PRCP GO:0004185 (TAS PMID:28321); MAS1 GO:0001595 angiotensin receptor activity (IBA/ISS, supported here by PMID:12829792), in preference to its TAS row for angiotensin type II receptor activity (PMID:3419518), a 1988 row that predates the identification of angiotensin-(1-7) as its ligand and looks like a possible upstream error worth checking; it is not used. GO:0005515 protein binding is never used. (5) GO:0002003 ON THE ARMS. GOA places GO:0002003 on ACE2 (IBA, IC), MME, PRCP and PREP (IEA), ENPEP and ANPEP (IBA), and CMA1 and CTSG (TAS, Reactome). The term's definition (conversion of angiotensinogen into mature angiotensin) covers each active angiotensin, so it is used on every protease annoton. Some of these enzymes also degrade angiotensins (neprilysin and ACE on angiotensin II and angiotensin-(1-7)), and that catabolic side is mentioned in role descriptions but not modelled as a separate step; GO has no angiotensin catabolic process term. (6) ALTERNATIVE PROTEASES AND WHAT WAS LEFT OUT. Chymase and cathepsin G are modelled as variants of the angiotensin II step (Reactome R-HSA-2022383, R-HSA-2022411); CMA1 and CTSG are on RGD's gene list. Neprilysin, PRCP and ACE are variants of the angiotensin-(1-7) step. PRCP is not on RGD's list but is the classical "angiotensinase C" with direct biochemical evidence (PMID:28321). Prolyl endopeptidase (PREP) was requested as a candidate but is left out: its only GO:0002003 row is IEA by orthology and no cached source documents its action on human angiotensins, so it stays context. Cathepsin D (CTSD) has renin-like activity on angiotensinogen in vitro but is not on RGD's list and no cached source was checked for it, so it is not a variant of the renin step. Other RGD-listed genes left out, by symbol: CTSA (cathepsin A; its gene review models a lysosomal serine carboxypeptidase and deamidase with no angiotensin-specific evidence cached), CPA3 (mast-cell carboxypeptidase A3, Reactome R-HSA-2028294 angiotensin I to angiotensin-(1-9), a minor side reaction with no human experimental GO row checked), cathepsin Z (Reactome R-HSA-2022381, not on RGD's list), NLN, THOP1 and RNPEP (oligopeptidases and arginyl aminopeptidase that RGD inherits from KEGG map04614 by IEA, with no reaction drawn on the RGD diagram), IGF2R (a renin and prorenin clearance receptor, which removes rather than performs the step), RENBP (renin-binding protein, now known to be N-acylglucosamine 2-epimerase; renin inhibition is a historical in vitro observation), LNPEP (IRAP, drawn by RGD as the angiotensin IV receptor; its gene review models it as a metalloaminopeptidase acting on peptide hormones, the angiotensin IV receptor claim is contested, and angiotensin IV signalling PW:0000458 is a separate pathway), and MRGPRD with the decarboxylated peptides angiotensin A and alamandine (Reactome R-HSA-9944540, R-HSA-9944473; the decarboxylase is unknown). AGTR1 and AGTR2 are in the referenced receptor module. (7) GO-CAM LINKS. gomodel:6246724f00000549 is linked on the REN and ACE (angiotensin II step) annotons. No production GO-CAM in gocams/index.tsv models ATP6AP2, CMA1, CTSG, MME, PRCP, ENPEP or ANPEP. ACE2 appears only in SARS-CoV-2 entry models (virus receptor activity) and MAS1 only in a CXCL17 chemokine model (gomodel:68fac5ed00003102); neither concerns angiotensin processing, so they are not linked. ACE's bradykinin-degradation activity (gomodel:6246724f00000632) belongs to modules/kallikrein_kinin_cascade.yaml. (8) GROUNDING. UniProt accessions come from genes/human/<GENE>/<GENE>-uniprot.txt for AGT and ATP6AP2 and from UniProt REST (reviewed human entries) for the rest. GO ids and labels were checked against .cache/rgd_pw/go-basic.obo (2026-07-26). Gene reviews exist for AGT, ATP6AP2, CTSA, CTSD and LNPEP only; REN, ACE, ACE2, CMA1, CTSG, MME, PRCP, ENPEP, ANPEP and MAS1 have none yet, which is curation follow-up for the project plan. PANTHER ids are omitted: every participant is a concrete human gene product and no family id was checked.