Metabolism of Angiotensinogen to Angiotensins

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R-HSA-2022377
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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
22389749 Molecular and Pathophysiological Features of Angiotensinogen: A Mini Review

Wu, C, Lu, H, Cassis, LA, Daugherty, A

N Am J Med Sci (Boston) 2011
21499495 Renin and cardiovascular disease: Worn-out path, or new direction

Alreja, G, Joseph, J

World J Cardiol 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, Oliveira, EB, Salgado, MC

Braz J Med Biol Res 2011
20418269 Aliskiren versus ramipril in hypertension

Verdecchia, P, Angeli, F, Mazzotta, G, Martire, P, Garofoli, M, Gentile, G, Reboldi, G

Ther Adv Cardiovasc Dis 2010
17509892 The intracellular renin-angiotensin system: a new paradigm

Kumar, R, Singh, VP, Baker, KM

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

Kramkowski, K, Mogielnicki, A, Buczko, W

J Physiol Pharmacol 2006
21945916 A new look at the renin-angiotensin system--focusing on the vascular system

Cat, AN, Touyz, RM

Peptides 2011
20380117 Is aliskiren superior to inhibitors of angiotensin-converting enzyme and angiotensin receptor blockers in renin-angiotensin system blockade?

Gerc, V, Buksa, M, Loza, V, Kulic, M

Med Arh 2009
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