Renin

Renin (etymology and pronunciation), also known as an angiotensinogenase, is an is_associated_with::enzyme that participates in the body's is_associated_with::renin-angiotensin aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that mediates is_associated_with::extracellular volume (i.e., that of the is_associated_with::blood plasma, is_associated_with::lymph and is_associated_with::interstitial fluid), and arterial is_associated_with::vasoconstriction. Thus, it regulates the body's mean arterial is_associated_with::blood pressure.

Renin is often improperly referred to as a hormone even though it has no peripheral receptors and rather has an enzymatic activity with which it hydrolyses is_associated_with::angiotensinogen to is_associated_with::angiotensin I.

Structure
The primary structure of renin precursor consists of 406 amino acids with a pre- and a is_associated_with::pro-segment carrying 20 and 46 amino acids, respectively. Mature renin contains 340 is_associated_with::amino acids and has a mass of 37 kDa.

Secretion
The enzyme renin is secreted by the is_associated_with::afferent arterioles of the kidney from specialized cells called granular cells of the is_associated_with::juxtaglomerular apparatus in response to three stimuli:
 * 1) A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by is_associated_with::baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
 * 2) A decrease in is_associated_with::sodium levels in the ultrafiltrate of the nephron. This flow is measured by the is_associated_with::macula densa of the is_associated_with::juxtaglomerular apparatus.
 * 3) is_associated_with::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


The renin enzyme circulates in the blood stream and breaks down (is_associated_with::hydrolyzes) is_associated_with::angiotensinogen secreted from the liver into the peptide is_associated_with::angiotensin I.

Angiotensin I is further cleaved in the lungs by endothelial-bound is_associated_with::angiotensin-converting enzyme (ACE) into is_associated_with::angiotensin II, the most vasoactive peptide. Angiotensin II is a potent constrictor of all blood vessels. It acts on the smooth muscle 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 is_associated_with::aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, and water, leading to raised blood volume and raised blood pressure. The RAS also acts on the CNS to increase water intake by stimulating is_associated_with::thirst, as well as conserving blood volume, by reducing urinary loss through the secretion of is_associated_with::vasopressin from the posterior is_associated_with::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 is_associated_with::renin-angiotensin system by cleaving is_associated_with::angiotensinogen, produced by the is_associated_with::liver, to yield is_associated_with::angiotensin I, which is further converted into is_associated_with::angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts is_associated_with::blood vessels, increases the secretion of ADH and is_associated_with::aldosterone, and stimulates the is_associated_with::hypothalamus to activate the thirst reflex, each leading to an increase in is_associated_with::blood 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 is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the is_associated_with::macula densa. The macula densa sense changes in volume delivery to the is_associated_with::distal tubule, and responds to a drop in tubular volume by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.

Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through beta-1 adrenoceptor activation.

Renin can bind to is_associated_with::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 is_associated_with::phosphorylation of serine and tyrosine residues of ATP6AP2.

The level of renin mRNA appears to be modulated by the binding of is_associated_with::HADHB, HuR and CP1 to a regulatory region in the 3' UTR.

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

Model organisms
is_associated_with::Model organisms have been used in the study of REN function. A is_associated_with::knockout mouse line, called Ren1Ren-1c Enhancer KO was generated. Male and female animals underwent a standardized is_associated_with::phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on is_associated_with::mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to is_associated_with::bacterial infection. A more detailed analysis of this line indicated plasma is_associated_with::creatinine was also increased and males had lower mean is_associated_with::arterial pressure than controls.

Clinical applications
An over-active renin-angiotension system leads to vasoconstriction and retention of is_associated_with::sodium and water. These effects lead to is_associated_with::hypertension. Therefore, is_associated_with::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 is_associated_with::differential diagnosis of is_associated_with::kidney cancer in a young patient with hypertension includes is_associated_with::juxtaglomerular cell tumor (is_associated_with::reninoma), is_associated_with::Wilms' tumor, and is_associated_with::renal cell carcinoma, all of which may produce renin.

Measurement
Renin is usually measured as the is_associated_with::plasma renin activity (PRA). PRA is measured specially in case of certain diseases that present with hypertension or is_associated_with::hypotension. PRA is also raised in certain tumors. A PRA measurement may be compared to a plasma is_associated_with::aldosterone concentration (PAC) as a PAC/PRA ratio.

Discovery and naming
The name renin = ren + -in, "is_associated_with::kidney" + "compound". The most common pronunciation in English is, but is also common. Renin was discovered, characterized, and named in 1898 by is_associated_with::Robert Tigerstedt, Professor of is_associated_with::Physiology, and his student, Per Bergman, at the is_associated_with::Karolinska Institute in is_associated_with::Stockholm.