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

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

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.

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.

Renin-Angiotensin System (RAS)

The Renin-angiotensin system, showing role of renin at bottom.

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. 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.

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.

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.

Genetics

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

Model organisms

Ren1 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Non-Invasive Blood Pressure	Abnormal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal
Citrobacter infection	Abnormal
All tests and analysis from

Model organisms have been used in the study of REN function. A knockout mouse line, called Ren1^{Ren-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.

Clinical applications

Main article: Renin inhibitor

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.

Measurement

Further information: Plasma renin activity

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

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

See also

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

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