Renin
251978
225079546
2008-07-11T19:52:37Z
Gaius Cornelius
293907
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{{Mergefrom|PRA (Medical)|date=March 2008}}
{{distinguish2|[[rennin]], the active enzyme in [[rennet]]}}
{{Protbox
|Name=Renin
|Photo=Renin.png
|Caption='''Molecular structure of renin'''
|HGNCid = 9958
|Symbol = REN
|AltSymbols =
|Names=Angiotensinogenase
|Chromosome = 1
|Arm = q
|Band = 32
|LocusSupplementaryData =
|Gene=
|Gene_type=
|Protein_length=406
|Molecular_weight=45060
|Structure=
|Type=
|Functions=Converts [[angiotensinogen]] to [[angiotensin I]]
|Domains=
|Motifs=[[SP motif]]
|Alternative_products=2 known isoforms produced from alternative splicing
|Catalytic_activity=
|Cofactors=
|Enzyme_regulation=
|Biophysicochemical_properties= [[Michaelis constant#Michaelis constant .27KM.27|''K''<sub>M</sub>]]=1 µmol/L for [[angiotensinogen]]
|Diseases=
|Pharmaceuticals=
|Biotechnology=
|Taxa= [[Homo sapiens]]; homologs many [[metazoan]] [[taxa]]
|Cells=
|Location= [[Extracellular]]
|Mods=
|Pathways=
|Interactions=
|Actions=
|Agonists=
|Antagonists=
|EntrezGene = 5972
|OMIM = 179820
|RefSeq = NM_000537
|UniProt = P00797
|PDB =
|ECnumber = 3.4.23.15
|Pages=
|Review=
}}
'''Renin''' (pronounced "Ree-nin" or "Rē-nin" ({{IPAEng|ˈriːnɨn}})), also known as '''Angiotensinogenase''', is a circulating [[enzyme]] that participates in the body's [[renin-angiotensin system]] (RAS) that mediates the following:
*Extracellular volume (i.e. that of your [[blood]], [[lymph]] and other body fluids), and
*Arterial vasoconstriction - the tone of the musculature of [[arteries]].
Thus it regulates one's (mean arterial) [[blood pressure]].
===Discovery===
Renin was discovered, characterized and named in 1898 by Robert Tigerstedt, Professor of [[Physiology]] at the [[Karolinska Institute]] in [[Stockholm]].{{Fact|date=March 2008}}
== Biochemistry and Physiology ==
===Structure===
The primary structure of renin precursor consists of 406 amino acids with a pre- and a pro- segment carrying 20 and 46 amino acids respectively. Mature renin contains 340 [[amino acid]]s and has a mass of 37 [[atomic mass unit|kD]].<ref>{{cite journal |author=Imai T, Miyazaki H, Hirose S, ''et al'' |title=Cloning and sequence analysis of cDNA for human renin precursor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=80 |issue=24 |pages=7405–9 |year=1983 |month=December |pmid=6324167 |pmc=389959 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6324167}}</ref>
===Secretion:===
The enzyme is secreted by the [[kidney]] from specialized cells of the [[nephrons]], called [[juxtaglomerular cells]] in response to:
*A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by [[baroreceptors]] (pressure sensitive cells). This is the most causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
*A decrease in [[sodium chloride]] levels in the ultra-filtrate of the nephron. This flow is measured by the [[macula densa]] of the [[juxtaglomerular apparatus]].
*[[Sympathetic nervous system]] activity, that also controls blood pressure, acting through the β<sub>1</sub> adrenergic receptors.
Human Renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of prorenin and a regulated pathway for the secretion of mature renin.<ref>{{cite journal |author=Pratt RE, Flynn JA, Hobart PM, Paul M, Dzau VJ |title=Different secretory pathways of renin from mouse cells transfected with the human renin gene |journal=J. Biol. Chem. |volume=263 |issue=7 |pages=3137–41 |year=1988 |month=March |pmid=2893797 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2893797}}</ref>
===The Renin-[[Angiotensin]]-[[Aldosterone]] Axis / [[Renin-angiotensin system|Renin-Angiotensin System]](RAS):===
*''Mechanism of action of Renin:''
The enzyme circulates in the blood stream and breaks down ([[hydrolyzes]]) [[angiotensinogen]] secreted from the liver into the peptide [[angiotensin I]].
*''Rest of the RAS:''
Angiotensin I is further cleaved in the lungs by endothelial bound [[angiotensin converting enzyme]] (ACE) into [[angiotensin II]], the most vasoactive peptide.<ref>{{cite journal |author=Fujino T, Nakagawa N, Yuhki K, ''et al'' |title=Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP |journal=J. Clin. Invest. |volume=114 |issue=6 |pages=805–12 |year=2004 |month=September |pmid=15372104 |pmc=516260 |doi=10.1172/JCI21382 |url=http://www.jci.org/cgi/content/full/114/6/805?ijkey=e3335f0a9a7b40386d49e7172910ea6345c9342a}}</ref><ref>Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. pp.2118-2119.[http://home.mdconsult.com/das/book/56203699-6/view/1201?sid=460067115 Full Text with MDConsult subscription]</ref> Angiotensin II is a potent constrictor of the all blood vessels. It acts on the musculature and there by raises the resistance posed by these arteries to the heart. The heart, trying to overcome this increase in its 'load' works more vigorously, causing the blood pressure to rise. Angiotensin II also acts on the adrenal glands to and releases [[Aldosterone]], which stimulates the epithelial cells of the kidneys to increase re-absorption of salt and water leading to raised blood volume and raised blood pressure. The RAS also acts on the CNS to increase water intake by stimulating [[thirst]], as well as conserving blood volume, by reducing urinary loss through the secretion of [[ADH]] from the posterior [[pituitary]] gland.
The normal concentration in adult human [[blood plasma|plasma]] is 1.98-24.6 ng/L in the upright position.<ref>Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. [http://142.238.64.246/detail.asp?RecNumber=723&TestFind=renin&SortBy=Name&ViewAlpha=&ParNum= Renin Direct]</ref>
==Function==
Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the [[liver]], to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts [[blood vessel]]s, increases the secretion of [[antidiuretic hormone|ADH]] and [[aldosterone]], and stimulates the [[hypothalamus]] to activate the thirst reflex, each leading to an increase in [[blood pressure]].
Renin is secreted from juxtaglomerular cells (of the afferent arterioles), which are activated via signaling (the release of prostaglandins) from the [[macula densa]], which respond to the rate of fluid flow through the [[distal tubule]], by decreases in renal perfusion pressure (through stretch receptors in the vascular wall), and by nervous stimulation, mainly through beta-1 receptor activation. A drop in the rate of flow past the macula densa implies a drop in renal filtration pressure. Renin's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
Renin can bind to [[ATP6AP2]], which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin. In addition, renin binding results in [[phosphorylation]] of serine and tyrosine residues of ATP6AP2.<ref>{{cite journal |author=Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD |title=Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin |journal=J. Clin. Invest. |volume=109 |issue=11 |pages=1417–27 |year=2002 |month=June |pmid=12045255 |pmc=150992 |doi=10.1172/JCI14276 |url=}}</ref>
==Genetics==
The [[gene]] for renin, ''REN'', spans 12 kb of DNA and contains 8 introns.<ref>{{cite journal |author=Hobart PM, Fogliano M, O'Connor BA, Schaefer IM, Chirgwin JM |title=Human renin gene: structure and sequence analysis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=81 |issue=16 |pages=5026–30 |year=1984 |month=August |pmid=6089171 |pmc=391630 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6089171}}</ref> It produces several [[mRNA]] that encode different REN [[isoform]]s.
==Clinical implications==
An over-active renin-angiotension system leads to vasoconstriction and retention of [[sodium]] and water. These effects lead to [[hypertension]]. Therefore, [[renin inhibitor]]s can be used for the treatment of hypertension. This is measured by the [[PRA (Medical)|plasma renin activity(PRA}]].
[[Aliskiren]], is a first-in-class oral renin inhibitor, developed by [[Novartis]] in conjunction with the [[biotech]] company [[Speedel]]. It was approved by the US [[Food and Drug Administration]] in 2007. It is an octanamide, is the first known representative of a new class of completely non-peptide, low-molecular weight, orally active transition-state renin inhibitors. Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of ≈24 hours. [[Tekturna]] has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. It was approved by the United States FDA on [[6 March]] [[2007]], and for use in Europe on [[27 August]] [[2007]]. Its trade name is Tekturna in the USA, and Rasilez in the UK.
==See also==
* [[Angiotensin-converting enzyme]]
* [[PRA (Medical)|plasma renin activity]].
==References==
{{reflist}}
==External links==
* {{MeshName|Renin}}
* {{eMedicineDictionary|renin}}
{{hormones}}
{{Cardiovascular system}}
{{Renal physiology}}
{{Aspartic acid proteases}}
[[Category:EC 3.4.23]]
[[Category:Hormones of the kidneys]]
[[Category:Peptide hormones]]
[[Category:Renal physiology]]
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