renin

renin Identifiers EC number 3.4.23.15 CAS number 9015-94-5 IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures Gene Ontology AmiGO / EGO Search PMC articles PubMed articles

edit renin PDB rendering based on 2ren. Available structures 2bks, 2g24, 2ren, 2iko, 2g1y, 2g20, 2g26, 2g1n, 1bil, 2iku, 2g1o, 2g1r, 1bim, 2fs4, 2il2, 1hrn, 2bkt, 2g27, 1rne, 2g21, 1bbs, 2g1s, 2i4q, 2g22 Identifiers Symbols REN; FLJ10761 External IDs OMIM: 179820 MGI: 97898 HomoloGene: 20151 Gene ontology Molecular function • peptidase activity • renin activity • receptor binding • aspartic-type endopeptidase activity Cellular component • membrane • intracellular membrane-bounded organelle • extracellular space • extracellular region • cytoplasm Biological process • regulation of blood pressure • kidney development • regulation of blood volume by renin-angiotensin • regulation of MAPKKK cascade • cell maturation • proteolysis • drinking behavior • angiotensin maturation • hormone-mediated signaling Orthologs Species Human Mouse Entrez 5972 19701 Ensembl ENSG00000143839 ENSMUSG00000070645 UniProt P00797 P06281 RefSeq NM_000537 (mRNA) NM_031192 (mRNA) NP_000528 (protein) NP_112469 (protein) Location Chr 1: 202.39 - 202.4 Mb Chr 1: 135.25 - 135.26 Mb PubMed search [2] [3]

Renin (pronounced /ˈriːnɨn/ REE-nin), also known as angiotensinogenase is an enzyme that participates in the body's renin-angiotensin system (RAS) 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.

Discovery

Renin was discovered, characterized and named in 1898 by Robert Tigerstedt, Professor of Physiology at the Karolinska Institute in Stockholm.^{[citation needed]}

Citation - Tigerstedt R, Bergman PG. Niere und Kreislauf. Scand Arch Physiol. 1898;8:223-271

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.^[1]

Secretion

The peptide hormone is secreted by the kidney from specialized cells called granular cells of the juxtaglomerular apparatus in 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 chloride levels in the ultra-filtrate of the nephron. This flow is measured by the macula densa of the juxtaglomerular apparatus.
• Sympathetic nervous system activity, 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.^[2]

The Renin-Angiotensin-Aldosterone Axis / Renin-Angiotensin System (RAS)

The Renin-angiotensin system, showing role of renin at bottom.^[3]

• Mechanism of action of Renin:

The enzyme circulates in the blood stream and breaks down (hydrolyzes) angiotensinogen secreted 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.^[4][5] 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 and releases Aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts 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 Vasopressin from the posterior pituitary gland.

The normal concentration in adult human plasma is 1.98-24.6 ng/L in the upright position.^[6]

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 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 phosphorylation of serine and tyrosine residues of ATP6AP2.^[7]

Genetics

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

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. This is measured by the plasma renin activity(PRA).

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. Aliskiren 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.

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.^[9]

See also

• Angiotensin-converting enzyme
• plasma renin activity.

References

External links

• MeSH Renin
• renin at eMedicine Dictionary

v • d • e PDB Gallery 2bks: CRYSTAL STRUCTURE OF RENIN-PF00074777 COMPLEX   2g24: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   2ren: STRUCTURE OF RECOMBINANT HUMAN RENIN, A TARGET FOR CARDIOVASCULAR-ACTIVE DRUGS, AT 2.5 ANGSTROMS RESOLUTION   2iko: Crystal Structure of Human Renin Complexed with Inhibitor   2g1y: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   2g20: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring   2g26: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   2g1n: Ketopiperazine-based renin inhibitors: Optimization of the ""C"" ring   1bil: CRYSTALLOGRAPHIC STUDIES ON THE BINDING MODES OF P2-P3 BUTANEDIAMIDE RENIN INHIBITORS   2iku: Crystal Structure of Human Renin Complexed with Inhibitors   2g1o: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   2g1r: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring   1bim: CRYSTALLOGRAPHIC STUDIES ON THE BINDING MODES OF P2-P3 BUTANEDIAMIDE RENIN INHIBITORS   2fs4: Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring   2il2: Crystal Structure of Human Renin Complexed with Inhibitor   1hrn: HIGH RESOLUTION CRYSTAL STRUCTURES OF RECOMBINANT HUMAN RENIN IN COMPLEX WITH POLYHYDROXYMONOAMIDE INHIBITORS   2bkt: CRYSTAL STRUCTURE OF RENIN-PF00257567 COMPLEX   2g27: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   1rne: THE CRYSTAL STRUCTURE OF RECOMBINANT GLYCOSYLATED HUMAN RENIN ALONE AND IN COMPLEX WITH A TRANSITION STATE ANALOG INHIBITOR   2g21: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring   1bbs: X-RAY ANALYSES OF PEPTIDE INHIBITOR COMPLEXES DEFINE THE STRUCTURAL BASIS OF SPECIFICITY FOR HUMAN AND MOUSE RENINS   2g1s: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring   2i4q: Human renin/PF02342674 complex   2g22: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring