Renin: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{SIB}} +, -{{EH}} +, -{{EJ}} +, -{{Editor Help}} +, -{{Editor Join}} +))
 
imported>Citation bot
m (Alter: isbn. Add: bibcode. You can use this bot yourself. Report bugs here. | Headbomb)
 
(2 intermediate revisions by 2 users not shown)
Line 1: Line 1:
{{Protbox
{{for|the places in Iran|Renin, Iran (disambiguation){{!}}Renin, Iran}}
  |Name=Renin
{{distinguish|text=[[rennin]], the active enzyme in [[rennet]]}}
  |Photo=Renin.png
{{Infobox_gene}}
  |Caption='''Molecular structure of renin'''
{{enzyme
  |HGNCid = 9958
| Name = renin
  |Symbol = REN
| EC_number = 3.4.23.15
  |AltSymbols =
| CAS_number = 9015-94-5
  |Names=Angiotensinogenase
| IUBMB_EC_number = 3/4/23/15
  |Chromosome = 1
| GO_code = 0004195
  |Arm = q
| image =  
  |Band = 32
| width =  
  |LocusSupplementaryData =
| caption =  
  |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=
}}
}}
{{SI}}
__NOTOC__
{{GS}}


'''Renin''' ([[#Discovery and naming|etymology and pronunciation]]), also known as an '''angiotensinogenase''', is an aspartic protease [[protein]] and [[enzyme]] secreted by the kidneys that participates in the body's [[renin–angiotensin system|renin–angiotensin–aldosterone system]] (RAAS)—also known as the renin–angiotensin–aldosterone axis—that mediates the volume of [[extracellular fluid]] ([[blood plasma]], [[lymph]] and [[interstitial fluid]]), and arterial [[vasoconstriction]]. Thus, it regulates the body's mean arterial [[blood pressure]].


Renin can also be referred to as a hormone, as it has a receptor, the (pro)renin receptor, also known as the renin receptor and prorenin receptor <ref name="PMID21087212">{{cite journal | vauthors = Nguyen G | title = Renin, (pro)renin and receptor: an update | journal = Clin Sci (Lond) | volume = 120 | issue = 5 | pages = 169–178 | date = Mar 2011 | pmid = 21087212 | doi = 10.1042/CS20100432 }}</ref> (see also below) as well as enzymatic activity with which it hydrolyzes [[angiotensinogen]] to [[angiotensin I]].


'''Renin''' (pronounced "Ree-nin" or "Rē-nin" ({{IPAEng|ˈriːnɨn}})), also known as '''angiotensinogenase''', is a circulating [[enzyme]] that participates in the [[renin-angiotensin system]] that mediates extracellular volume, arterial vasoconstriction, and consequently mean arterial blood pressure. The enzyme is secreted by the [[kidneys]] from specialized [[juxtaglomerular cells]] in response to decreases in [[glomerular filtration rate]] (a consequence of low blood volume), diminished filtered [[sodium chloride]] and [[sympathetic nervous system]] innervation. The enzyme circulates in the blood stream and hydrolyzes [[angiotensinogen]] secreted from the liver into the peptide [[angiotensin I]]. Angiotensin I is further cleaved in the lungs by endothelial bound [[angiotensin converting enzyme]] (ACE) into [[angiotensin II]], the final active peptide. <ref>Fujino T, Nakagawa N, Yuhki K, Hara A, Yamada T, Takayama K, Kuriyama S, Hosoki Y, Takahata O, Taniguchi T, Fukuzawa J, Hasebe N, Kikuchi K, Narumiya S and Ushikubi F. (2004) Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP. ''J. Clin. Invest.'' 114:805-812. [http://www.jci.org/cgi/content/full/114/6/805?ijkey=e3335f0a9a7b40386d49e7172910ea6345c9342a Full Text]</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> 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>


==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>Cloning and sequence analysis of cDNA for human renin precursor. ''; {{PMID|6324167}}'' {{PMID_free|6324167}}</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.
== Biochemistry and physiology ==


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>Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. ''2002 Jun; {{PMID|12045255}}'' {{PMID_free|12045255}}</ref>
===Structure===
The primary structure of renin precursor consists of 406 amino acids with a [[pre-segment|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|kDa]].<ref name="pmid6324167">{{cite journal | vauthors = Imai T, Miyazaki H, Hirose S, Hori H, Hayashi T, Kageyama R, Ohkubo H, Nakanishi S, Murakami K | title = Cloning and sequence analysis of cDNA for human renin precursor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 24 | pages = 7405–9 | date = Dec 1983 | pmid = 6324167 | pmc = 389959 | doi = 10.1073/pnas.80.24.7405 | bibcode = 1983PNAS...80.7405I }}</ref>


==Gene==
=== Secretion ===
The [[gene]] for renin, ''REN'', spans 12 kb of DNA and contains 8 introns.<ref>Human renin gene: structure and sequence analysis. ''1984 Aug; {{PMID|6089171}}'' {{PMID_free|6089171}}</ref> It produces several [[mRNA]] that encode different REN [[isoform]]s.
The enzyme renin is secreted by pericytes (mural cells) (1) in the vicinity of the [[afferent arterioles]] and similar microvessels of the kidney from specialized cells of the [[juxtaglomerular apparatus]]—the [[juxtaglomerular cell]]s, in response to three stimuli:
# 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 direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
# A decrease in [[sodium]] load delivered to the distal tubule. This load is measured by the [[macula densa]] of the [[juxtaglomerular apparatus]].
# [[Sympathetic nervous system]] activity, which also controls blood pressure, acting through the β<sub>1</sub> adrenergic receptors.


==Secretion==
Human renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of the precursor prorenin and a regulated pathway for the secretion of mature renin.<ref name="pmid2893797">{{cite journal | vauthors = 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 = The Journal of Biological Chemistry | volume = 263 | issue = 7 | pages = 3137–41 | date = Mar 1988 | pmid = 2893797 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2893797 }}</ref>
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>Different secretory pathways of renin from mouse cells transfected with the human renin gene. ''1988 Mar 5; {{PMID|2893797}}'' [http://www.jbc.org/cgi/reprint/263/7/3137 Free text (PDF - 1.3MB)]</ref>.


==Clinical implications==
===Renin–angiotensin system ===
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.
{{main|Renin–angiotensin system}}
[[File:Renin-angiotensin system in man shadow.svg|thumb|200px|left|The [[renin–angiotensin system]], showing role of renin at bottom.<ref name="isbn1-4160-2328-3">{{cite book |last1 = Boulpaep | first1 = E. L. | last2= Boron | first2 = W. F. | title = Medical physiology: a cellular and molecular approach | chapter = Integration of Salt and Water Balance; The Adrenal Gland | pages = 866–867, 1059 | publisher = Elsevier Saunders | location = St. Louis, MO | year =2005 | isbn = 978-1-4160-2328-9 | name-list-format = vanc }}</ref>]]


[[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.
The renin enzyme circulates in the blood stream and [[hydrolyzes]] (breaks down) [[angiotensinogen]] secreted from the liver into the peptide [[angiotensin I]].


==See also==
Angiotensin I is further cleaved in the lungs by endothelial-bound [[angiotensin-converting enzyme]] (ACE) into [[angiotensin II]], the most vasoactive peptide.<ref name="pmid15372104">{{cite journal | vauthors = Fujino T, Nakagawa N, Yuhki K, Hara A, Yamada T, Takayama K, Kuriyama S, Hosoki Y, Takahata O, Taniguchi T, Fukuzawa J, Hasebe N, Kikuchi K, Narumiya S, Ushikubi F | title = Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP | journal = The Journal of Clinical Investigation | volume = 114 | issue = 6 | pages = 805–12 | date = Sep 2004 | pmid = 15372104 | pmc = 516260 | doi = 10.1172/JCI21382 }}</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 all blood vessels. It acts on the smooth muscle and, therefore, 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 and releases [[aldosterone]], which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, 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 [[vasopressin]] from the posterior [[pituitary]] gland.
 
The normal concentration of renin in adult human [[blood plasma|plasma]] is 1.98–24.6&nbsp;ng/L in the upright position.<ref>Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. [deadlink]</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 [[angiotensin-converting enzyme|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's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
 
Renin is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the [[macula densa]]. The macula densa senses changes in sodium delivery to the [[distal tubule]], and responds to a drop in tubular sodium load by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.
 
Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through [[beta-2 adrenergic receptor]] (β<sub>1</sub> adrenoreceptor) activation.
 
The (pro)renin receptor to which renin and prorenin bind is  encoded by the gene [[ATP6ap2]], ATPase H(+)-transporting lysosomal accessory protein 2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin as well as non-hydrolytic activation of prorenin via a conformational change in prorenin which exposes the catalytic site to angiotensinogen substrate. In addition, renin and prorenin binding results in [[phosphorylation]] of serine and tyrosine residues of ATP6AP2.<ref name="pmid12045255">{{cite journal | vauthors = 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 = The Journal of Clinical Investigation | volume = 109 | issue = 11 | pages = 1417–27 | date = Jun 2002 | pmid = 12045255 | pmc = 150992 | doi = 10.1172/JCI14276 | url = http://www.jci.org/articles/view/14276/files/pdf }}</ref>
 
The level of renin mRNA appears to be modulated by the binding of [[HADHB]], [[ELAVL1|HuR]] and [[PCBP1|CP1]] to a [[Renin stability regulatory element (REN-SRE)|regulatory region]] in the [[Three prime untranslated region|3' UTR]].<ref name="pmid12933794">{{cite journal | vauthors = Adams DJ, Beveridge DJ, van der Weyden L, Mangs H, Leedman PJ, Morris BJ | title = HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression | journal = The Journal of Biological Chemistry | volume = 278 | issue = 45 | pages = 44894–903 | date = Nov 2003 | pmid = 12933794 | doi = 10.1074/jbc.M307782200 }}</ref>
 
== Genetics ==
 
The [[gene]] for renin, ''REN'', spans 12 kb of DNA and contains 8 introns.<ref name="pmid6089171">{{cite journal | vauthors = Hobart PM, Fogliano M, O'Connor BA, Schaefer IM, Chirgwin JM | title = Human renin gene: structure and sequence analysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 16 | pages = 5026–30 | date = Aug 1984 | pmid = 6089171 | pmc = 391630 | doi = 10.1073/pnas.81.16.5026 | bibcode = 1984PNAS...81.5026H }}</ref> It produces several [[mRNA]] that encode different REN [[isoform]]s.
 
Mutations in the ''REN'' gene can be inherited, and are a cause of a rare inherited kidney disease, so far found to be present in only 2 families. This disease is [[dominance (genetics)|autosomal dominant]], meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for [[dialysis]] or [[kidney transplantation]].  Many—but not all—patients and families with this disease suffer from an elevation in serum potassium and unexplained anemia relatively early in life.  Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40s while others may not go on dialysis until into their 70s.  This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.<ref name="pmid19664745">{{cite journal | vauthors = Zivná M, Hůlková H, Matignon M, Hodanová K, Vylet'al P, Kalbácová M, Baresová V, Sikora J, Blazková H, Zivný J, Ivánek R, Stránecký V, Sovová J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gübler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S | title = Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure | journal = Am. J. Hum. Genet. | volume = 85 | issue = 2 | pages = 204–13 | year = 2009 | pmid = 19664745 | pmc = 2725269 | doi = 10.1016/j.ajhg.2009.07.010 }}</ref>
 
===Model organisms===
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
|+ ''Ren1'' knockout mouse phenotype
|-
! Characteristic!! Phenotype
 
|-
| [[Homozygote]] viability || bgcolor="#488ED3"|Normal
|-
| Fertility || bgcolor="#488ED3"|Normal
|-
| Body weight || bgcolor="#488ED3"|Normal
|-
| [[Open Field (animal test)|Anxiety]] || bgcolor="#488ED3"|Normal
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
|-
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
|-
| Non-Invasive Blood Pressure || bgcolor="#C40000"|Abnormal<ref name="Non-Invasive Blood Pressure">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBSJ/non-invasive-blood-pressure/ |title=Non-Invasive Blood Pressure data for Ren1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#488ED3"|Normal
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
|-
| [[Haematology]] || bgcolor="#488ED3"|Normal
|-
| [[Micronucleus test]] || bgcolor="#488ED3"|Normal
|-
| Heart weight || bgcolor="#488ED3"|Normal
|-
| Skin Histopathology || bgcolor="#488ED3"|Normal
|-
| Brain histopathology || bgcolor="#488ED3"|Normal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBSJ/salmonella-challenge/ |title=''Salmonella'' infection data for Ren1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| ''[[Citrobacter]]'' infection || bgcolor="#C40000"|Abnormal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBSJ/citrobacter-challenge/ |title=''Citrobacter'' infection data for Ren1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal |doi=10.1111/j.1755-3768.2010.4142.x |title=The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice |year=2010 | vauthors = Gerdin AK |journal=Acta Ophthalmologica |volume=88 |pages=925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
 
[[Model organism]]s have been used in the study of REN function. A [[knockout mouse]] line, called ''Ren1<sup>Ren-1c Enhancer KO</sup>'' was generated.<ref name="pmid16895910">{{cite journal | vauthors = Adams DJ, Head GA, Markus MA, Lovicu FJ, van der Weyden L, Köntgen F, Arends MJ, Thiru S, Mayorov DN, Morris BJ | title = Renin enhancer is critical for control of renin gene expression and cardiovascular function | journal = The Journal of Biological Chemistry | volume = 281 | issue = 42 | pages = 31753–61 | date = Oct 2006 | pmid = 16895910 | doi = 10.1074/jbc.M605720200 }}</ref> Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty four tests were carried out on [[mutant]] mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to [[bacterial infection]].<ref name="mgp_reference" /> A more detailed analysis of this line indicated plasma [[creatinine]] was also increased and males had lower mean [[arterial pressure]] than controls.<ref name="pmid16895910" />
 
== Clinical applications ==
{{Main|Renin inhibitor}}
 
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.<ref>[http://pharmaxchange.info/presentations/dri.html Presentation on Direct Renin Inhibitors as Antihypertensive Drugs] {{webarchive|url=https://web.archive.org/web/20101207071030/http://pharmaxchange.info/presentations/dri.html |date=2010-12-07 }}</ref><ref name="pmid19715410">{{cite journal | vauthors = Ram CV | title = Direct inhibition of renin: a physiological approach to treat hypertension and cardiovascular disease | journal = Future Cardiology | volume = 5 | issue = 5 | pages = 453–65 | date = Sep 2009 | pmid = 19715410 | doi = 10.2217/fca.09.31 }}</ref> This is measured by the [[PRA (Medical)|plasma renin activity]] (PRA).
 
In current medical practice, the renin–angiotensin–aldosterone system's overactivity (and resultant hypertension) is more commonly reduced using either ACE inhibitors (such as ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor. ACE inhibitors or ARBs are also part of the standard treatment after a heart attack.
 
The [[differential diagnosis]] of [[kidney cancer]] in a young patient with hypertension includes [[juxtaglomerular cell tumor]] ([[reninoma]]), [[Wilms' tumor]], and [[renal cell carcinoma]], all of which may produce renin.<ref name="pmid19098017">{{cite journal | vauthors = Méndez GP, Klock C, Nosé V | title = Juxtaglomerular cell tumor of the kidney: case report and differential diagnosis with emphasis on pathologic and cytopathologic features | journal = International Journal of Surgical Pathology | volume = 19 | issue = 1 | pages = 93–8 | date = Feb 2011 | pmid = 19098017 | doi = 10.1177/1066896908329413 }}</ref>
 
=== Measurement ===
{{Further|Plasma renin activity}}
Renin is usually measured as the [[plasma renin activity]] (''PRA''). PRA is measured specially in case of certain diseases that present with [[Hypertension#Role of renin|hypertension]] or [[hypotension]]. PRA is also raised in certain tumors.<ref>Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. Renin Direct.</ref> A PRA measurement may be compared to a plasma [[aldosterone]] concentration (PAC) as a ''PAC/PRA ratio''.
 
==Discovery and naming==
The name ''renin'' = ''[[wikt:ren#Latin|ren]]'' + ''[[wikt:-in#Suffix|-in]]'', "[[kidney]]" + "[[chemical compound|compound]]". The most common pronunciation in English is {{IPAc-en|ˈ|r|iː|n|ᵻ|n}} (long ''e''); {{IPAc-en|ˈ|r|ɛ|n|ᵻ|n}} (short ''e'') is also common, but using {{IPAc-en|ˈ|r|iː|n|ᵻ|n}} allows one to reserve {{IPAc-en|ˈ|r|ɛ|n|ᵻ|n}} for ''[[rennin]]''. Renin was discovered, characterized, and named in 1898 by [[Robert Tigerstedt]], Professor of [[Physiology]], and his student, Per Bergman, at the [[Karolinska Institute]] in [[Stockholm]].<ref name="pmid11390864">{{cite journal | vauthors = Phillips MI, Schmidt-Ott KM | title = The Discovery of Renin 100 Years Ago | journal = News in Physiological Sciences | volume = 14 | issue =  | pages = 271–274 | date = Dec 1999 | pmid = 11390864 }}</ref><ref>{{cite journal | last1 = Tigerstedt | first1 = Robert | last2 = Bergman | first2 = Per G. | title = Niere und Kreislauf | trans-title = Kidney and Circulation | language = German | journal = Skandinavisches Archiv für Physiologie [Scandinavian Archives of Physiology] | volume = 8 | pages = 223–271 | year = 1898 | doi =10.1111/j.1748-1716.1898.tb00272.x | name-list-format = vanc }}</ref>
 
== See also ==
* [[Angiotensin-converting enzyme]]
* [[Angiotensin-converting enzyme]]
* [[Plasma renin activity]]
* [[Renin inhibitor]]
* [[Renin stability regulatory element (REN-SRE)]]


==References==
== References ==
<references />
{{reflist|33em}}
(1) Human kidney pericytes produce renin ; Stefanska A, Kenyon C, Christian HC, Buckley C, Shaw I, Mullins JJ, Péault B. Kidney Int. 2016 Dec; 90(6):1251-1261


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK53700/  GeneReviews/NCBI/NIH/UW entry on Familial Juvenile Hyperuricemic Nephropathy Type 2] 
* [https://www.ncbi.nlm.nih.gov/omim/179820,613092  OMIM entries on Familial Juvenile Hyperuricemic Nephropathy Type 2]
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A01.007 A01.007]
* {{MeshName|Renin}}
* {{MeshName|Renin}}
* {{eMedicineDictionary|renin}}


{{hormones}}
{{Authority control}}
{{PDB Gallery|geneid=5972}}
{{Hormones}}
{{Cardiovascular system}}
{{Cardiovascular system}}
{{Renal physiology}}
{{Renal physiology}}
{{Aspartic acid proteases}}
{{Aspartic acid proteases}}
 
{{Enzymes}}
{{Angiotensin receptor modulators}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


[[Category:EC 3.4.23]]
[[Category:EC 3.4.23]]
Line 95: Line 166:
[[Category:Peptide hormones]]
[[Category:Peptide hormones]]
[[Category:Renal physiology]]
[[Category:Renal physiology]]
[[Category:Endocrinology]]
[[Category:Genes mutated in mice]]
 
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
 
[[de:Renin]]
[[dv:ރީނިން]]
[[es:Renina]]
[[fr:Rénine]]
[[it:Renina]]
[[nl:Renine]]
[[ja:レニン]]
[[pl:Renina]]
[[pt:Renina]]
[[ru:Ренин]]
[[simple:Renin]]
[[sr:Ренин]]
[[sv:Renin]]

Latest revision as of 22:34, 29 December 2018

For the places in Iran, see Renin, Iran.
Not to be confused with rennin, the active enzyme in rennet.
VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
renin
Identifiers
EC number3.4.23.15
CAS number9015-94-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the renin–angiotensin–aldosterone axis—that mediates the volume of extracellular fluid (blood plasma, lymph and interstitial fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.

Renin can also be referred to as a hormone, as it has a receptor, the (pro)renin receptor, also known as the renin receptor and prorenin receptor [1] (see also below) as well as enzymatic activity with which it hydrolyzes angiotensinogen to angiotensin I.



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 acids and has a mass of 37 kDa.[2]

Secretion

The enzyme renin is secreted by pericytes (mural cells) (1) in the vicinity of the afferent arterioles and similar microvessels of the kidney from specialized cells of the juxtaglomerular apparatus—the juxtaglomerular cells, in response to three stimuli:

  1. 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 direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
  2. A decrease in sodium load delivered to the distal tubule. This load is measured by the macula densa of the juxtaglomerular apparatus.
  3. Sympathetic nervous system activity, which 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 the precursor prorenin and a regulated pathway for the secretion of mature renin.[3]

Renin–angiotensin system

Main article: Renin–angiotensin system

File:Renin-angiotensin system in man shadow.svg

The renin enzyme circulates in the blood stream and hydrolyzes (breaks down) angiotensinogen secreted from the liver into the peptide angiotensin I.

Angiotensin I is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the most vasoactive peptide.[5][6] Angiotensin II is a potent constrictor of all blood vessels. It acts on the smooth muscle and, therefore, 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 and releases aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, 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 vasopressin from the posterior pituitary gland.

The normal concentration of renin in adult human plasma is 1.98–24.6 ng/L in the upright position.[7]

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 vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood 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 is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the macula densa. The macula densa senses changes in sodium delivery to the distal tubule, and responds to a drop in tubular sodium load by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.

Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through beta-2 adrenergic receptor (β1 adrenoreceptor) activation.

The (pro)renin receptor to which renin and prorenin bind is encoded by the gene ATP6ap2, ATPase H(+)-transporting lysosomal accessory protein 2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin as well as non-hydrolytic activation of prorenin via a conformational change in prorenin which exposes the catalytic site to angiotensinogen substrate. In addition, renin and prorenin binding results in phosphorylation of serine and tyrosine residues of ATP6AP2.[8]

The level of renin mRNA appears to be modulated by the binding of HADHB, HuR and CP1 to a regulatory region in the 3' UTR.[9]

Genetics

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.[10] It produces several mRNA that encode different REN isoforms.

Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease, so far found to be present in only 2 families. This disease is autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for dialysis or kidney transplantation. Many—but not all—patients and families with this disease suffer from an elevation in serum potassium and unexplained anemia relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40s while others may not go on dialysis until into their 70s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.[11]

Model organisms

Model organisms have been used in the study of REN function. A knockout mouse line, called Ren1Ren-1c Enhancer KO was generated.[17] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][18] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to bacterial infection.[15] A more detailed analysis of this line indicated plasma creatinine was also increased and males had lower mean arterial pressure than controls.[17]

Clinical applications

Main article: Renin inhibitor

An over-active renin-angiotension system leads to vasoconstriction and retention of sodium and water. These effects lead to hypertension. Therefore, renin inhibitors can be used for the treatment of hypertension.[19][20] This is measured by the plasma renin activity (PRA).

In current medical practice, the renin–angiotensin–aldosterone system's overactivity (and resultant hypertension) is more commonly reduced using either ACE inhibitors (such as ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor. ACE inhibitors or ARBs are also part of the standard treatment after a heart attack.

The differential diagnosis of kidney cancer in a young patient with hypertension includes juxtaglomerular cell tumor (reninoma), Wilms' tumor, and renal cell carcinoma, all of which may produce renin.[21]

Measurement

Further information: Plasma renin activity

Renin is usually measured as the plasma renin activity (PRA). PRA is measured specially in case of certain diseases that present with hypertension or hypotension. PRA is also raised in certain tumors.[22] A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.

Discovery and naming

The name renin = ren + -in, "kidney" + "compound". The most common pronunciation in English is /ˈriːnɪn/ (long e); /ˈrɛnɪn/ (short e) is also common, but using /ˈriːnɪn/ allows one to reserve /ˈrɛnɪn/ for rennin. Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology, and his student, Per Bergman, at the Karolinska Institute in Stockholm.[23][24]

See also

References

  1. ↑ Nguyen G (Mar 2011). "Renin, (pro)renin and receptor: an update". Clin Sci (Lond). 120 (5): 169–178. doi:10.1042/CS20100432. PMID 21087212.
  2. ↑ Imai T, Miyazaki H, Hirose S, Hori H, Hayashi T, Kageyama R, Ohkubo H, Nakanishi S, Murakami K (Dec 1983). "Cloning and sequence analysis of cDNA for human renin precursor". Proceedings of the National Academy of Sciences of the United States of America. 80 (24): 7405–9. Bibcode:1983PNAS...80.7405I. doi:10.1073/pnas.80.24.7405. PMC 389959. PMID 6324167.
  3. ↑ Pratt RE, Flynn JA, Hobart PM, Paul M, Dzau VJ (Mar 1988). "Different secretory pathways of renin from mouse cells transfected with the human renin gene". The Journal of Biological Chemistry. 263 (7): 3137–41. PMID 2893797.
  4. ↑ Boulpaep EL, Boron WF (2005). "Integration of Salt and Water Balance; The Adrenal Gland". Medical physiology: a cellular and molecular approach. St. Louis, MO: Elsevier Saunders. pp. 866–867, 1059. ISBN 978-1-4160-2328-9.
  5. ↑ Fujino T, Nakagawa N, Yuhki K, Hara A, Yamada T, Takayama K, Kuriyama S, Hosoki Y, Takahata O, Taniguchi T, Fukuzawa J, Hasebe N, Kikuchi K, Narumiya S, Ushikubi F (Sep 2004). "Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP". The Journal of Clinical Investigation. 114 (6): 805–12. doi:10.1172/JCI21382. PMC 516260. PMID 15372104.
  6. ↑ Brenner & Rector's The Kidney, 7th ed., Saunders, 2004, pp. 2118-2119 Full Text with MDConsult subscription
  7. ↑ Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. [deadlink]
  8. ↑ Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD (Jun 2002). "Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin". The Journal of Clinical Investigation. 109 (11): 1417–27. doi:10.1172/JCI14276. PMC 150992. PMID 12045255.
  9. ↑ Adams DJ, Beveridge DJ, van der Weyden L, Mangs H, Leedman PJ, Morris BJ (Nov 2003). "HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression". The Journal of Biological Chemistry. 278 (45): 44894–903. doi:10.1074/jbc.M307782200. PMID 12933794.
  10. ↑ Hobart PM, Fogliano M, O'Connor BA, Schaefer IM, Chirgwin JM (Aug 1984). "Human renin gene: structure and sequence analysis". Proceedings of the National Academy of Sciences of the United States of America. 81 (16): 5026–30. Bibcode:1984PNAS...81.5026H. doi:10.1073/pnas.81.16.5026. PMC 391630. PMID 6089171.
  11. ↑ Zivná M, Hůlková H, Matignon M, Hodanová K, Vylet'al P, Kalbácová M, Baresová V, Sikora J, Blazková H, Zivný J, Ivánek R, Stránecký V, Sovová J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gübler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S (2009). "Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure". Am. J. Hum. Genet. 85 (2): 204–13. doi:10.1016/j.ajhg.2009.07.010. PMC 2725269. PMID 19664745.
  12. ↑ "Non-Invasive Blood Pressure data for Ren1". Wellcome Trust Sanger Institute.
  13. ↑ "Salmonella infection data for Ren1". Wellcome Trust Sanger Institute.
  14. ↑ "Citrobacter infection data for Ren1". Wellcome Trust Sanger Institute.
  15. ↑ 15.0 15.1 15.2 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  16. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  17. ↑ 17.0 17.1 Adams DJ, Head GA, Markus MA, Lovicu FJ, van der Weyden L, Köntgen F, Arends MJ, Thiru S, Mayorov DN, Morris BJ (Oct 2006). "Renin enhancer is critical for control of renin gene expression and cardiovascular function". The Journal of Biological Chemistry. 281 (42): 31753–61. doi:10.1074/jbc.M605720200. PMID 16895910.
  18. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
  19. ↑ Presentation on Direct Renin Inhibitors as Antihypertensive Drugs Archived 2010-12-07 at the Wayback Machine.
  20. ↑ Ram CV (Sep 2009). "Direct inhibition of renin: a physiological approach to treat hypertension and cardiovascular disease". Future Cardiology. 5 (5): 453–65. doi:10.2217/fca.09.31. PMID 19715410.
  21. ↑ Méndez GP, Klock C, Nosé V (Feb 2011). "Juxtaglomerular cell tumor of the kidney: case report and differential diagnosis with emphasis on pathologic and cytopathologic features". International Journal of Surgical Pathology. 19 (1): 93–8. doi:10.1177/1066896908329413. PMID 19098017.
  22. ↑ Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. Renin Direct.
  23. ↑ Phillips MI, Schmidt-Ott KM (Dec 1999). "The Discovery of Renin 100 Years Ago". News in Physiological Sciences. 14: 271–274. PMID 11390864.
  24. ↑ Tigerstedt R, Bergman PG (1898). "Niere und Kreislauf" [Kidney and Circulation]. Skandinavisches Archiv für Physiologie [Scandinavian Archives of Physiology] (in German). 8: 223–271. doi:10.1111/j.1748-1716.1898.tb00272.x.

(1) Human kidney pericytes produce renin ; Stefanska A, Kenyon C, Christian HC, Buckley C, Shaw I, Mullins JJ, Péault B. Kidney Int. 2016 Dec; 90(6):1251-1261

External links

Lua error in Module:Authority_control at line 788: attempt to index field 'wikibase' (a nil value).

Retrieved from "https://www.wikidoc.org/index.php?title=Renin&oldid=1530387"