Renin, also known as an angiotensinogenase, is an enzyme that participates in the body's
renin-angiotensin system—also known as the renin-angiotensin-aldosterone axis—that
mediates extracellular volume, and arterial vasoconstriction. Thus, it regulates the body's
mean arterial blood pressure. Renin is often improperly referred to as a
hormone although it has no peripheral receptors and rather has an enzymatic activity with
which it hydrolyses angiotensinogen to angiotensin I.
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 enzyme renin is secreted by the afferent arterioles of the kidney from specialized
cells called granular cells of the juxtaglomerular apparatus in response to three stimuli:
A decrease in arterial blood pressure as detected by baroreceptors. This is the most direct
causal link between blood pressure and renin secretion.
A decrease in sodium chloride levels in the ultrafiltrate of the nephron. This flow is
measured by the macula densa of the juxtaglomerular apparatus.
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 angiotensinogen secreted from
the liver into the peptide angiotensin I. Angiotensin I is further cleaved in the lungs
by endothelial-bound angiotensin-converting enzyme into 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
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 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'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 macula densa. The macula densa sense changes in volume delivery to the 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 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 Model organisms have been used in the study
of REN function. A knockout mouse line, called Ren1Ren-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
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.
In current medical practice, the renin-angiotensin-aldosterone-System's overactivity is more commonly reduced using
either ACE inhibitors or angiotensin II receptor blockers 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, Wilms' tumor, and renal cell carcinoma, all of which may
produce renin. Measurement
Renin is usually measured as the plasma renin activity. 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 as a
PAC/PRA ratio. Discovery
Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of
Physiology and his student, Per Bergman, at the Karolinska Institute in Stockholm.
See also Angiotensin-converting enzyme
Plasma renin activity Renin inhibitor
Renin stability regulatory element References
External links GeneReviewsNIH/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 Renin at the US National Library of Medicine
Medical Subject Headings renin at eMedicine Dictionary