Renin

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 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 which 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