Renin
Encyclopedia
Renin 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
.
s and has a mass of 37 kDa
.
from specialized cells called granular cells of the juxtaglomerular apparatus
via 3 responses:
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.
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, 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.
, 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 vessel
s, 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.
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
.
for renin, REN, spans 12 kb of DNA and contains 8 introns. It produces several mRNA that encode different REN isoforms.
and water. These effects lead to hypertension
. Therefore, renin inhibitor
s 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 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.
. PRA is also raised in certain tumors. A PRA measurement may be compared to a plasma aldosterone
concentration (PAC) as a PAC/PRA ratio.
at the Karolinska Institute in Stockholm
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that participates in the body's renin-angiotensin system
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
(RAS) -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
volume (i.e., that of the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
, lymph
Lymph
Lymph is considered a part of the interstitial fluid, the fluid which lies in the interstices of all body tissues. Interstitial fluid becomes lymph when it enters a lymph capillary...
and interstitial fluid
Interstitial fluid
Interstitial fluid is a solution that bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular fluid...
), and arterial vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
. Thus, it regulates the body's mean arterial blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
.
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 acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and has a mass of 37 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
.
Secretion
The peptide hormone is secreted by the kidneyKidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
from specialized cells called granular cells of the juxtaglomerular apparatus
Juxtaglomerular apparatus
The juxtaglomerular apparatus is a microscopic structure in the kidney, which regulates the function of each nephron. The juxtaglomerular apparatus is named for its proximity to the glomerulus: it is found between the vascular pole of the renal corpuscle and the returning distal convoluted tubule...
via 3 responses:
- 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 chlorideSodium chlorideSodium chloride, also known as salt, common salt, table salt or halite, is an inorganic compound with the formula NaCl. Sodium chloride is the salt most responsible for the salinity of the ocean and of the extracellular fluid of many multicellular organisms...
levels in the ultra-filtrate of the nephron. This flow is measured by the macula densaMacula densaIn the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule at the point of return of the nephron to the vascular pole of its parent glomerulus, ....
of the juxtaglomerular apparatusJuxtaglomerular apparatusThe juxtaglomerular apparatus is a microscopic structure in the kidney, which regulates the function of each nephron. The juxtaglomerular apparatus is named for its proximity to the glomerulus: it is found between the vascular pole of the renal corpuscle and the returning distal convoluted tubule...
. - Sympathetic nervous systemSympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
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 (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. 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
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, 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
Thirst
Thirst is the craving for fluids, resulting in the basic instinct of animals to drink. It is an essential mechanism involved in fluid balance. It arises from a lack of fluids and/or an increase in the concentration of certain osmolites, such as salt...
, as well as conserving blood volume, by reducing urinary loss through the secretion of Vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
from the posterior pituitary gland.
The normal concentration of renin in adult human plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
is 1.98-24.6 ng/L in the upright position.
Function
Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, 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 vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s, increases the secretion of ADH and aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, and stimulates the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
to activate the thirst reflex, each leading to an increase in blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
.
Renin is secreted from kidney cells, which are activated via signaling from the macula densa
Macula densa
In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule at the point of return of the nephron to the vascular pole of its parent glomerulus, ....
, 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
ATP6AP2
The renin receptor also known as ATPase H-transporting lysosomal accessory protein 2, or the prorenin receptor, is a protein that in humans is encoded by the ATP6AP2 gene.- Function :The renin receptor binds renin and prorenin...
, 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
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of serine and tyrosine residues of ATP6AP2.
The level of renin mRNA appears to be modulated by the binding of HADHB
HADHB
Trifunctional enzyme subunit beta, mitochondrial also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene....
, HuR
ELAVL1
ELAV-like protein 1 or HuR is a protein that in humans is encoded by the ELAVL1 gene.-Further reading:...
and CP1
PCBP1
Poly-binding protein 1 is a protein that in humans is encoded by the PCBP1 gene.-Further reading:...
to a regulatory region
Renin stability regulatory element (REN-SRE)
The Renin stability regulatory element is a cis-acting element identified in the 3'untranslated region of the renin gene. It acts to regulate the levels of renin protein produced in the cell...
in the 3' UTR
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
.
Genetics
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for renin, REN, spans 12 kb of DNA and contains 8 introns. It produces several mRNA that encode different REN isoforms.
Clinical applications
An over-active renin-angiotension system leads to vasoconstriction and retention of sodiumSodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and water. These effects lead to hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. Therefore, renin inhibitor
Renin inhibitor
Renin inhibitor, or inhibitors of renin, are a new group of pharmaceuticals that are used primarily in treatment of hypertension.They act on the juxtaglomerular cells of kidney, which produce renin in response to decreased blood flow....
s can be used for the treatment of hypertension. This is measured by the plasma renin activity
PRA (Medical)
Plasma renin activity , also known as the renin assay or random plasma renin, is a measure of the activity of the plasma enzyme renin, which plays a major role in the body's regulation of blood pressure, thirst, and urine output. PRA is sometimes measured, specially in case of certain diseases...
(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
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
of kidney cancer
Kidney cancer
Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...
in a young patient with hypertension includes juxtaglomerular cell tumor
Juxtaglomerular cell tumor
Juxtaglomerular cell tumor is a rare kidney cancer that typically secretes renin. It involves the juxtaglomerular cells. It often causes hypertension, in adults and children, although among causes of hypertension it is rare. Its malignant potential is uncertain.-History:Juxtaglomerular cell tumor...
(reninoma), Wilms' tumor
Wilms' tumor
Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon who first described this kind of tumor....
, and renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
, all of which may produce renin.
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 hypotensionHypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
. PRA is also raised in certain tumors. A PRA measurement may be compared to a plasma aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
concentration (PAC) as a PAC/PRA ratio.
Discovery
Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of PhysiologyPhysiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
at the Karolinska Institute in Stockholm
Stockholm
Stockholm is the capital and the largest city of Sweden and constitutes the most populated urban area in Scandinavia. Stockholm is the most populous city in Sweden, with a population of 851,155 in the municipality , 1.37 million in the urban area , and around 2.1 million in the metropolitan area...
.
See also
- Renin inhibitorRenin inhibitorRenin inhibitor, or inhibitors of renin, are a new group of pharmaceuticals that are used primarily in treatment of hypertension.They act on the juxtaglomerular cells of kidney, which produce renin in response to decreased blood flow....
- Angiotensin-converting enzymeAngiotensin-converting enzymeAngiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
- Plasma renin activity.
- Renin stability regulatory element (REN-SRE)Renin stability regulatory element (REN-SRE)The Renin stability regulatory element is a cis-acting element identified in the 3'untranslated region of the renin gene. It acts to regulate the levels of renin protein produced in the cell...
External links
- GeneReviews/NCBI/NIH/UW entry on Familial Juvenile Hyperuricemic Nephropathy Type 2
- OMIM entries on Familial Juvenile Hyperuricemic Nephropathy Type 2
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: A01.007