Metabolism of Angiotensinogen to Angiotensins Angiotensinogen, a prohormone, is synthesized and secreted mainly by the liver but also from other tissues (reviewed in Fyhrquist and Saijonmaa 2008, Cat and Touyz 2011). Renin, an aspartyl protease specific for angiotensinogen, is secreted into the bloodstream by juxtaglomerular cells of the kidney in response to a drop in blood pressure. Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Circulating renin can also bind the membrane-localized (pro)renin receptor (ATP6AP2) which increases its catalytic activity. After cleavage of angiotensinogen to angiotensin I by renin, two C-terminal amino acid residues of angiotensin I are removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion.<br>More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified (reviewed in Kramkowski et al. 2006, Kumar et al. 2007, Fyhrquist and Saijonmaa 2008, Becari et al. 2011). Chymase, cathepsin G, and cathepsin X (cathepsin Z) can each cleave angiotensin I to yield angiotensin II. Angiotensin-converting enzyme 2 (ACE2) cleaves 1 amino acid residue from angiotensin I (angiotensin-(1-10)) to yield angiotensin-(1-9), which can be cleaved by ACE to yield angiotensin-(1-7). ACE2 can also cleave angiotensin II to yield angiotensin-(1-7). Neprilysin can cleave either angiotensin-(1-9) or angiotensin I to yield angiotensin-(1-7). Angiotensin-(1-7) binds the MAS receptor (MAS1, MAS proto-oncogene) and, interestingly, produces effects opposite to those produced by angiotensin II.<br>Aminopeptidase A (APA, ENPEP) cleaves angiotensin II to yield angiotensin III (angiotensin-(2-8)), which is then cleaved by aminopeptidase N (APN, ANPEP) yielding angiotensin IV (angiotensin-(3-8)). Angiotensin IV binds the AT4 receptor (AT4R, IRAP, LNPEP, oxytocinase).<br>Inhibitors of renin (e.g. aliskiren) and ACE (e.g. lisinopril, ramipril) are currently used to treat hypertension (reviewed in Gerc et al. 2009, Verdecchia et al. 2010, Alreja and Joseph 2011). Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed12676165 Pubmed17229979 Pubmed17509892 Pubmed18793332 Pubmed20380117 Pubmed20418269 Pubmed21499495 Pubmed21945916 Pubmed21956534 Pubmed22389749 Pubmed22410251 Reactome Database ID Release 432022377 Reactome, http://www.reactome.org ReactomeREACT_147707 Reviewed: Joseph, J, 2012-08-06 PathwayStep3226 PathwayStep3227 PathwayStep3224 PathwayStep3225 PathwayStep3228 PathwayStep3213 PathwayStep3214 PathwayStep3215 PathwayStep3216 PathwayStep3217 PathwayStep3218 PathwayStep3219 PathwayStep3221 PathwayStep3220 PathwayStep3223 PathwayStep3222 Renin Hydrolyzes Angiotensinogen to Yield Angiotensin I Renin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10) Neprilysin Hydrolyzes Angiotensin I to Yield Angiotensin-(1-7) Cathepsin Z (Cathepsin X) Hydrolyzes Angiotensin I to Yield Angiotensin II ACE2 Hydrolyzes Angiotensin I to Yield Angiotensin-(1-9) ACE Hydrolyzes Angiotensin-(1-9) to Yield Angiotensin-(1-7) Neprilysin Hydrolyzes Angiotensin-(1-9) to Yield Angiotensin-(1-7) Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) Cathepsin G Hydrolyzes Angiotensin I to Yield Angiotensin II Chymase Hydrolyzes Angiotensin I to Yield Angiotensin II Prorenin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10) ENPEP Hydrolyzes Angiotensin II to Yield Angiotensin III ANPEP Hydrolyzes Angiotensin III to Yield Angiotensin IV ACE2 Hydrolyzes Angiotensin II to Yield Angiotensin-(1-7) Mast Cell Carboxypeptidase Hydrolyzes Angiotensin I to Yield Angiotensin-(1-9)