renin

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.{{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 = 7405–7409 |date = Dec 1983 |pmid = 6324167 |pmc = 389959 |doi = 10.1073/pnas.80.24.7405 |bibcode = 1983PNAS...80.7405I |doi-access = free }}

The enzyme renin is secreted by pericytes 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.{{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 = 3137–3141 |date = Mar 1988 |doi = 10.1016/S0021-9258(18)69046-5 |pmid = 2893797 |url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2893797 |doi-access = free }}{{Dead link|date=March 2022 |bot=InternetArchiveBot |fix-attempted=yes }}

{{main|Renin–angiotensin system}}

File:Renin-angiotensin system in man shadow.svg, showing role of renin at bottom{{cite book | vauthors = Boulpaep EL, Boron WF |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 }}]]

The renin enzyme circulates in the bloodstream 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.{{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 = 805–812 |date = Sep 2004 |pmid = 15372104 |pmc = 516260 |doi = 10.1172/JCI21382}}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] {{Webarchive |url=https://web.archive.org/web/20150207204614/http://home.mdconsult.com/das/book/56203699-6/view/1201?sid=460067115 |date=2015-02-07 }} 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, and so for the same cardiac output, the blood pressure will 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.

{{cite web |url=http://lrc.stjoes.ca/detail.asp?RecNumber=723&TestFind=renin&SortBy=Name&ViewAlpha=&ParNum= |publisher=Hamilton Regional Laboratory Medicine Program |title=Laboratory Reference Centre Manual }}{{Dead link |date=March 2019 |bot=InternetArchiveBot |fix-attempted=yes }}

Renin activates the renin–angiotensin system by using its endopeptidase activity to cleave the peptide bonds between leucine and valine residues in angiotensinogen,{{cite journal | vauthors = Zhou MS, Schulman IH, Zeng Q | title = Link between the renin-angiotensin system and insulin resistance: implications for cardiovascular disease | journal = Vascular Medicine | volume = 17 | issue = 5 | pages = 330–341 | date = October 2012 | pmid = 22814999 | doi = 10.1177/1358863X12450094 | doi-access = free }} 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 β₁ adrenoreceptor activation.{{cite journal | vauthors = Kopp U, Aurell M, Nilsson IM, Ablad B | title = The role of beta-1-adrenoceptors in the renin release response to graded renal sympathetic nerve stimulation | journal = Pflügers Archiv | volume = 387 | issue = 2 | pages = 107–113 | date = September 1980 | pmid = 6107894 | doi = 10.1007/BF00584260 | s2cid = 25873845 }}

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.{{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 = 1417–1427 | date = Jun 2002 | pmid = 12045255 | pmc = 150992 | doi = 10.1172/JCI14276 }}

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.{{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 = 44894–44903 | date = Nov 2003 | pmid = 12933794 | doi = 10.1074/jbc.M307782200 | doi-access = free }}

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.{{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 = 5026–5030 | date = Aug 1984 | pmid = 6089171 | pmc = 391630 | doi = 10.1073/pnas.81.16.5026 | bibcode = 1984PNAS...81.5026H | doi-access = free }} 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 have 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.{{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 = 204–213 | year = 2009 | pmid = 19664745 | pmc = 2725269 | doi = 10.1016/j.ajhg.2009.07.010 }}

{{Main|Renin inhibitor}}

An over-active renin-angiotensin 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.[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 }}{{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 = 453–465 | date = Sep 2009 | pmid = 19715410 | doi = 10.2217/fca.09.31 }} 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.{{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 = 93–98 | date = Feb 2011 | pmid = 19098017 | doi = 10.1177/1066896908329413 | s2cid = 38702564 }}

{{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 or hypotension. PRA is also raised in certain tumors.Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. Renin Direct. A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.

The name renin = ren + -in, "kidney" + "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.{{cite journal | vauthors = Phillips MI, Schmidt-Ott KM | title = The Discovery of Renin 100 Years Ago | journal = News in Physiological Sciences | volume = 14 | pages = 271–274 | date = Dec 1999 | issue = 6 | doi = 10.1152/physiologyonline.1999.14.6.271 | pmid = 11390864 | s2cid = 22118033 }}{{cite journal | vauthors = Tigerstedt R, Bergman PG | title = Niere und Kreislauf | trans-title = Kidney and Circulation | language = de | journal = Skandinavisches Archiv für Physiologie | volume = 8 | pages = 223–271 | year = 1898 | doi =10.1111/j.1748-1716.1898.tb00272.x }}

• Angiotensin-converting enzyme
• Plasma renin activity
• Renin inhibitor
• Renin stability regulatory element (REN-SRE)

{{reflist|30em}}

{{refbegin}}

• {{cite journal | vauthors = Stefanska A, Kenyon C, Christian HC, Buckley C, Shaw I, Mullins JJ, Péault B | title = Human kidney pericytes produce renin | journal = Kidney International | volume = 90 | issue = 6 | pages = 1251–1261 | date = December 2016 | pmid = 27678158 | pmc = 5126097 | doi = 10.1016/j.kint.2016.07.035 }}
• {{cite book | vauthors = Kmoch S, Živná M, Bleyer AJ | chapter = Familial Juvenile Hyperuricemic Nephropathy Type 2 | veditors = Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A | title = GeneReviews [Internet] | location = Seattle (WA) | publisher = University of Washington, Seattle | date = 2015 | pages = 1993–2014 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK53700/ | pmid = 21473025 }}

{{refend}}

• The MEROPS online database for peptidases and their inhibitors: [https://archive.today/20121223104239/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A01.007 A01.007]
• {{MeshName|Renin}}
• {{PDBe-KB2|P00797|Renin}}

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Category:EC 3.4.23

Category:Hormones of the kidneys

Category:Peptide hormones

Category:Renal physiology

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