PDB rendering based on 2ren
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that mediates extracellular volume (i.e., that of the blood plasma, lymph and interstitial fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.
Biochemistry and physiology 1
- Structure 1.1
- Secretion 1.2
- Renin-angiotensin system 1.3
- Function 2
- Model organisms 3.1
Clinical applications 4
- Measurement 4.1
- Discovery and naming 5
- See also 6
- References 7
- External links 8
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 kDa.
- 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 chloride levels in the ultrafiltrate of the nephron. This flow is measured by the macula densa of the juxtaglomerular apparatus.
- Sympathetic nervous system activity, which also controls blood pressure, acting through the beta1 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.
Angiotensin I is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the most vasoactive peptide. 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.
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 sense changes in volume delivery to the distal tubule, and responds to a drop in tubular volume 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-1 adrenoceptor activation.
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.
Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease. 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 40's while others may not go on dialysis until into their 70’s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.
|Non-Invasive Blood Pressure||Abnormal|
|Glucose tolerance test||Normal|
|Auditory brainstem response||Normal|
|All tests and analysis from|
knockout mouse line, called Ren1Ren-1c Enhancer KO was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. 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. A more detailed analysis of this line indicated plasma creatinine was also increased and males had lower mean arterial pressure than controls.
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. 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.
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. 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 , but is also common. 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.
- Angiotensin-converting enzyme
- Plasma renin activity
- Renin inhibitor
- Renin stability regulatory element (REN-SRE)
- 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.
- 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.
- 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.
- 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.
- Brenner & Rector's The Kidney, 7th ed., Saunders, 2004, pp. 2118-2119 Full Text with MDConsult subscription
- Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. [deadlink]
- 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.
- 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.
- 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.
- 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.
- "Non-Invasive Blood Pressure data for Ren1". Wellcome Trust Sanger Institute.
- infection data for Ren1"Salmonella". Wellcome Trust Sanger Institute.
- infection data for Ren1"Citrobacter". Wellcome Trust Sanger Institute.
- Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7.
- Mouse Resources Portal, Wellcome Trust Sanger Institute.
- 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.
- van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224.
- Presentation on Direct Renin Inhibitors as Antihypertensive Drugs
- Ram CV (Sep 2009). "Direct inhibition of renin: a physiological approach to treat hypertension and cardiovascular disease". Future Cardiology 5 (5): 453–65.
- 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.
- Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. Renin Direct.
- Phillips MI, Schmidt-Ott KM (Dec 1999). "The Discovery of Renin 100 Years Ago". News in Physiological Sciences 14: 271–274.
- Tigerstedt R, Bergman PG (1898). "Niere und Kreislauf" [Scandinavian Archives of Physiology]. Skandinavisches Archiv für Physiologie (in German) 8: 223–271.
- GeneReviews/NCBI/NIH/UW entry on Familial Juvenile Hyperuricemic Nephropathy Type 2
- OMIM entries on Familial Juvenile Hyperuricemic Nephropathy Type 2
- The MEROPS online database for peptidases and their inhibitors: A01.007
- Renin at the US National Library of Medicine Medical Subject Headings (MeSH)