Renin

From Wikipedia, the free encyclopedia

Not to be confused with rennin, the active enzyme in rennet.

Renin
Image:Renin.png 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:	K_M=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 low blood volume or low body NaCl content, 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. <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. Full Text</ref> 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. <ref>Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. pp.2118-2119.Full Text with MDConsult subscription</ref> The normal concentration in human plasma is 1.0-2.5 mg/ml.

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

[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. <ref>Cloning and sequence analysis of cDNA for human renin precursor. ; PubMed Free text</ref>

[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 responsable for angiotensin II conversion, due to the huge surface of endothelium it possesses on the many capillaries used for 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 the juxtaglomerular cells, via signalling (the release of prostaglandins) from the macula densa, which respond to the rate of fluid flow through the distal tubule. If the rate of flow past the macula densa drops, then this will indicate a drop in filtration pressure in the kidneys. Renin's primary function therefore is 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 4-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. <ref>Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. 2002 Jun; PubMed Free text</ref>

[edit] Gene

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.<ref>Human renin gene: structure and sequence analysis. 1984 Aug; PubMed Free text</ref> 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 <ref>Different secretory pathways of renin from mouse cells transfected with the human renin gene. 1988 Mar 5; PubMed Free text (PDF - 1.3MB)</ref>.

[edit] Clinical implications

An overactive 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.

Many analysts believe the first renin inhibitor to be launched will be Novartis' Rasilez (aliskiren), a first-in-class oral renin inhibitor currently undergoing Phase III clinical trials. Rasilez, 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. Rasilez has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver.

[edit] See also

Angiotensin-converting enzyme

[edit] References

Hormones and endocrine glands - edit

Hypothalamus: - TRH - CRH - GnRH - GHRH - somatostatin - dopamine | Posterior pituitary: vasopressin - oxytocin - lipotropin | Anterior pituitary: GH - ACTH - TSH - LH - FSH - prolactin - MSH - endorphins - lipotropin

Stomach: gastrin | Duodenum: CCK - GIP - secretin - motilin - VIP | Ileum: enteroglucagon | Liver: IGF-1

Placenta: hCG - HPL - estrogen - progesterone

Adipose tissue: leptin, adiponectin

Target-derived NGF, BDNF, NT-3

Urinary system - Kidney - edit
Renal capsule \| Renal cortex \| Renal medulla (Renal sinus, Renal pyramids) \| Renal calyx \| Renal pelvis
Nephron - Renal corpuscle (Glomerulus, Bowman's capsule) → Proximal tubule → Loop of Henle → Distal convoluted tubule → Collecting ducts Juxtaglomerular apparatus (Macula densa, Juxtaglomerular cells, Extraglomerular mesangial cells) Renal circulation - Renal artery → Interlobar arteries → Arcuate arteries → Cortical radial arteries → Afferent arterioles → Glomerulus → Efferent arterioles → Vasa recta → Arcuate vein→ Renal vein
Renal physiology
Filtration - Ultrafiltration \| Countercurrent exchange Hormones effecting filtration - Antidiuretic hormone (ADH) \| Aldosterone \| Atrial natriuretic peptide Endocrine - Renin \| Erythropoietin (EPO) \| Calcitriol (Active vitamin D) \| Prostaglandins
Assessing Renal function / Measures of dialysis
Glomerular filtration rate \| Creatinine clearance \| Renal clearance ratio \| Urea reduction ratio \| Kt/V \| Standardized Kt/V \| Hemodialysis product