Renin is not commonly referred to as a
hormone, albeit it having a receptor, the (pro)renin receptor, also known as the
renin receptor and prorenin receptor (see also below),[4] as well as enzymatic activity with which it
hydrolyzesangiotensinogen 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.[5]
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 direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
Human renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of the precursor
prorenin and a regulated pathway for the secretion of mature renin.[6]
The renin enzyme circulates in the bloodstream and
hydrolyzes (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 (ACE) into
angiotensin II, the most vasoactive peptide.[8][9] 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, and so for the same cardiac output, the blood pressure will 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.[10]
Function
Renin activates the
renin–angiotensin system by using its endopeptidase activity to cleave the peptide bonds between leucine and valine residues in angiotensinogen,[11] 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 senses changes in sodium delivery to the
distal tubule, and responds to a drop in tubular sodium load 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
β1 adrenoreceptor activation.[12]
The (pro)renin receptor to which renin and prorenin bind is encoded by the gene
ATP6ap2, ATPase H(+)-transporting lysosomal accessory protein 2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin as well as non-hydrolytic activation of prorenin via a conformational change in prorenin which exposes the catalytic site to angiotensinogen substrate. In addition, renin and prorenin binding results in
phosphorylation of serine and tyrosine residues of ATP6AP2.[13]
The
gene for renin, REN, spans 12 kb of DNA and contains 8 introns.[15] It produces several
mRNA that encode different REN
isoforms.
Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease, so far found to be present in only 2 families. This disease is
autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for
dialysis or
kidney transplantation. Many—but not all—patients and families with this disease have an elevation in serum potassium and unexplained anemia relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40s while others may not go on dialysis until into their 70s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.[16]
An over-active renin-angiotensin 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.[17][18] 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.
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.[20] A PRA measurement may be compared to a plasma
aldosterone concentration (PAC) as a PAC/PRA ratio.
^Boulpaep EL, Boron WF (2005). "Integration of Salt and Water Balance; The Adrenal Gland". Medical physiology: a cellular and molecular approach. St. Louis, MO: Elsevier Saunders. pp. 866–867, 1059.
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^Kopp U, Aurell M, Nilsson IM, Ablad B (September 1980). "The role of beta-1-adrenoceptors in the renin release response to graded renal sympathetic nerve stimulation". Pflügers Archiv. 387 (2): 107–113.
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^Ram CV (Sep 2009). "Direct inhibition of renin: a physiological approach to treat hypertension and cardiovascular disease". Future Cardiology. 5 (5): 453–465.
doi:
10.2217/fca.09.31.
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^Méndez GP, Klock C, Nosé V (Feb 2011). "Juxtaglomerular cell tumor of the kidney: case report and differential diagnosis with emphasis on pathologic and cytopathologic features". International Journal of Surgical Pathology. 19 (1): 93–98.
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10.1177/1066896908329413.
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^Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual. Renin Direct.
Kmoch S, Živná M, Bleyer AJ (2015).
"Familial Juvenile Hyperuricemic Nephropathy Type 2". In Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. pp. 1993–2014.
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