Caption=Molecular structure of renin
HGNCid = 9958
Symbol = REN
Chromosome = 1
Arm = q
Band = 32
angiotensinogento angiotensin I
Alternative_products=2 known isoforms produced from alternative splicing
Biophysicochemical_properties= "K"M=1 µmol/L for
Homo sapiens; homologs many metazoan taxa
EntrezGene = 5972
OMIM = 179820
RefSeq = NM_000537
UniProt = P00797
ECnumber = 188.8.131.52
Renin (pronounced "Ree-nin" or "Rē-nin" (IPAEng|ˈriːnɨn)), also known as Angiotensinogenase, is a circulating
enzymethat participates in the body's renin-angiotensin system(RAS) that mediates the following:
*Extracellular volume (i.e. that of your
blood, lymphand other body fluids), and
*Arterial vasoconstriction - the tone of the musculature of
arteries.Thus it regulates one's (mean arterial) blood pressure.
Renin was discovered, characterized and named in 1898 by Robert Tigerstedt, Professor of
Physiologyat the Karolinska Institutein Stockholm.Fact|date=March 2008
Biochemistry and Physiology
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 acids and has a mass of 37 kD. [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]
The peptide hormone is secreted by the
kidneyfrom specialized cells called granular cells of the juxtaglomerular apparatusin 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 chloridelevels in the ultra-filtrate of the nephron. This flow is measured by the macula densaof the juxtaglomerular apparatus.
Sympathetic nervous systemactivity, that also controls blood pressure, acting through the β1 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. [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]
Angiotensin- AldosteroneAxis / Renin-Angiotensin System(RAS):=
*"Mechanism of action of Renin:"The enzyme circulates in the blood stream and breaks down (
hydrolyzes) angiotensinogensecreted 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. [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] [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] ] Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature and thereby 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 too 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 Vasopressinfrom the posterior pituitarygland.
The normal concentration in adult human plasma is 1.98-24.6 ng/L in the upright position. [Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. [http://184.108.40.206/detail.asp?RecNumber=723&TestFind=renin&SortBy=Name&ViewAlpha=&ParNum= Renin Direct] ]
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 vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamusto 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 phosphorylationof serine and tyrosine residues of ATP6AP2. [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=]
genefor renin, "REN", spans 12 kb of DNA and contains 8 introns. [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] It produces several mRNAthat encode different REN isoforms.
An over-active renin-angiotension system leads to vasoconstriction and retention of
sodiumand water. These effects lead to hypertension. Therefore, renin inhibitors can be used for the treatment of hypertension. This is measured by the plasma renin activity(PRA}. Aliskiren, is a first-in-class oral renin inhibitor, developed by Novartisin conjunction with the biotechcompany Speedel. It was approved by the US Food and Drug Administrationin 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. Tekturnahas 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.
* plasma renin activity.
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