renin

Renin
PDB rendering based on 2ren.
Available structures PDB 1BBS, 1BIL, 1BIM, 1HRN, 1RNE, 2BKS, 2BKT, 2FS4, 2G1N, 2G1O, 2G1R, 2G1S, 2G1Y, 2G20, 2G21, 2G22, 2G24, 2G26, 2G27, 2I4Q, 2IKO, 2IKU, 2IL2, 2REN, 2V0Z, 2V10, 2V11, 2V12, 2V13, 2V16, 2X0B, 3D91, 3G6Z, 3G70, 3G72, 3GW5, 3K1W, 3KM4, 3OAD, 3OAG, 3OOT, 3OQF, 3OQK
Identifiers
Symbols	REN; FLJ10761; HNFJ2
External IDs	OMIM: 179820 MGI: 97898 HomoloGene: 20151 GeneCards: REN Gene
EC number	3.4.23.15
Gene Ontology Molecular function • aspartic-type endopeptidase activity • receptor binding • insulin-like growth factor receptor binding • peptidase activity Cellular component • extracellular region • extracellular space • membrane • cytoplasmic part Biological process • kidney development • mesonephros development • angiotensin maturation • proteolysis • response to stress • regulation of blood pressure • male gonad development • response to drug • regulation of MAPKKK cascade • response to cAMP • response to cGMP Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5972	19701
Ensembl	ENSG00000143839	ENSMUSG00000070645
UniProt	P00797	P06281
RefSeq (mRNA)	NM_000537	NM_031192.3
RefSeq (protein)	NP_000528	NP_112469.1
Location (UCSC)	Chr 1: 204.12 – 204.14 Mb	Chr 1: 135.25 – 135.26 Mb
PubMed search	[2]	[3]

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

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 via 3 responses:

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 causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
2. 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.
3. 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 prorenin and a regulated pathway for the secretion of mature renin.^[2]

Renin-Angiotensin System (RAS)

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

The renin enzyme circulates in the blood stream and breaks down (hydrolyzes) 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.^[4][5] Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature 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 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.^[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 kidney cells, which are activated via signaling from the macula densa, which responds 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 sympathetic 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]

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.^[8]

Genetics

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.^[9] It produces several mRNA that encode different REN isoforms.

Clinical applications

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.^[10][11] 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.^[12]

Measurement

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.^[13] A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.

Discovery

Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology at the Karolinska Institute in Stockholm.^[14][15]

See also

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

References

External links

• 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
• 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