Renin

[ree-nin]

Renin (pronounced "Ree-nin" or "Rē-nin" ()), also known as Angiotensinogenase, is a circulating enzyme that participates in the body's renin-angiotensin system (RAS) that mediates the following:

Extracellular volume (i.e. that of your blood, lymph and other body fluids), and
Arterial vasoconstriction - the tone of the musculature of arteries.

Thus it regulates one's (mean arterial) blood pressure.

Discovery

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

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 kD.

Secretion:

The peptide hormone is secreted by the kidney from specialized cells called granular cells of the juxtaglomerular apparatus in response to:

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).
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.
Sympathetic nervous system activity, that also controls blood pressure, acting through the β₁ 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.

The Renin-Angiotensin-Aldosterone Axis / Renin-Angiotensin System(RAS):

Mechanism of action of Renin:

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

Rest of the RAS:

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 thereby 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 too and releases Aldosterone, which stimulates the epithelial cells of the kidneys to increase re-absorption of salt 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 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 juxtaglomerular cells (of the afferent arterioles), which are activated via signaling (the release of prostaglandins) from the macula densa, which respond 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 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.

Genetics

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

Clinical implications

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}.

Aliskiren, is a first-in-class oral renin inhibitor, developed by Novartis in conjunction with the biotech company Speedel. It was approved by the US Food and Drug Administration in 2007. It is 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. Tekturna has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. It was approved by the United States FDA on 6 March 2007, and for use in Europe on 27 August 2007. Its trade name is Tekturna in the USA, and Rasilez in the UK.