Renin

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Renin
Molecular structure of renin
Symbol(s):	REN
Other names:	Angiotensinogenase
Genetic data
Locus:	Chr. 1 q32
Protein Structure/Function
Protein length:	406 (Amino Acids)
Molecular Weight:	45060 (Da)
Functions:	Converts angiotensinogen to angiotensin I
Motifs:	SP motif
Alternative Products:	2 known isoforms produced from alternative splicing
Other
Taxa expressing:	Homo sapiens; homologs many metazoan taxa
Subcellular localization:	Extracellular
Biophysicochemical properties:	KM=1 µmol/L for angiotensinogen
Database Links
EC number:	3.4.23.15
Codes:	EntrezGene 5972; Mendelian Inheritance in Man (OMIM) 179820; RefSeq NM_000537; UniProt P00797

Renin, also known as angiotensinogenase, is a circulating enzyme released mainly by juxtaglomerular cells in the JGA of the kidneys in response to high blood volume or decreased serum NaCl concentration, mediated through the rapid release of prostaglandins. Although it has hormone-like actions, it cleaves a protein precursor in the circulation rather than working on a cellular target. Thus it is not truly a hormone. ^[1] Sympathetic activation of membrane β1- and α1-adrenergic receptors on JGA cells also cause renin release, probably by altering tubular sodium content or macula densa function. ^[2] The normal concentration in human plasma is 1.0-2.5 mg/ml. Renin is pronounced "Ree-nin" (IPA: [ˈɹinɪn]).

Contents 1 Structure 2 Function 3 Gene 4 Secretion 5 Clinical implications 6 See also 7 References 8 External links

[edit] 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 kD. ^[3]

[edit] Function

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced in the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme. This is a membrane-bound enzyme present on the surface of the vascular endothelium of blood vessels throughout the body. The lung is the primary organ responsible for angiotensin II conversion, due to the large endothelial surface area of the many capillaries used in gas exchange. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, leading to increased blood pressure.

Renin is secreted from juxtaglomerular cells, which are activated via signalling (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 four-fold 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.^[4]

[edit] Gene

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.^[5] It produces several mRNA that encode different REN isoforms.

[edit] Secretion

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 ^[6].

[edit] Clinical implications

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.

Tekturna (aliskiren), formerly known as Rasilez, is a first-in-class oral renin inhibitor. Tekturna was developed by Novartis in conjunction with the biotech company Speedel, and was approved by the US Food and Drug Administration in 2007. Tekturna, 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. Tekturna was approved by the United States FDA on 6 March 2007.

[edit] See also

• Angiotensin-converting enzyme

[edit] References

1. ^ 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. Full Text
2. ^ Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. pp.2118-2119.Full Text with MDConsult subscription
3. ^ Cloning and sequence analysis of cDNA for human renin precursor. ; PubMed Free text
4. ^ Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. 2002 Jun; PubMed Free text
5. ^ Human renin gene: structure and sequence analysis. 1984 Aug; PubMed Free text
6. ^ Different secretory pathways of renin from mouse cells transfected with the human renin gene. 1988 Mar 5; PubMed Free text (PDF - 1.3MB)

[edit] External links

• MeSH Renin
• Dictionary at eMedicine renin