Reactome | Metabolism of Angiotensinogen to Angiotensins

Metabolism of Angiotensinogen to Angiotensins

Stable Identifier

R-HSA-2022377

DOI

10.3180/REACT_147707.1

Type

Pathway

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

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Metabolism of Angiotensinogen to Angiotensins

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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.
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.
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).
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).

Literature References

PubMed ID	Title	Journal	Year
21499495	Renin and cardiovascular disease: Worn-out path, or new direction Joseph, J, Alreja, G	World J Cardiol	2011
22389749	Molecular and Pathophysiological Features of Angiotensinogen: A Mini Review Daugherty, A, Lu, H, Cassis, LA, Wu, C	N Am J Med Sci (Boston)	2011
12676165	The renin-angiotensin and the kallikrein-kinin systems Campbell, DJ	Int J Biochem Cell Biol	2003
22410251	Recent advances involving the renin-angiotensin system Crowley, SD, Coffman, TM	Exp. Cell Res.	2012
21956534	Alternative pathways for angiotensin II generation in the cardiovascular system Becari, C, Salgado, MC, Oliveira, EB	Braz J Med Biol Res	2011
20418269	Aliskiren versus ramipril in hypertension Reboldi, G, Angeli, F, Garofoli, M, Martire, P, Mazzotta, G, Verdecchia, P, Gentile, G	Ther Adv Cardiovasc Dis	2010
17509892	The intracellular renin-angiotensin system: a new paradigm Baker, KM, Kumar, R, Singh, VP	Trends Endocrinol Metab	2007
18793332	Renin-angiotensin system revisited Fyhrquist, F, Saijonmaa, O	J Intern Med	2008
17229979	The physiological significance of the alternative pathways of angiotensin II production Buczko, W, Kramkowski, K, Mogielnicki, A	J Physiol Pharmacol	2006
21945916	A new look at the renin-angiotensin system--focusing on the vascular system Touyz, RM, Cat, AN	Peptides	2011
20380117	Is aliskiren superior to inhibitors of angiotensin-converting enzyme and angiotensin receptor blockers in renin-angiotensin system blockade? Kulic, M, Gerc, V, Buksa, M, Loza, V	Med Arh	2009