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The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
,
fluid In physics, a fluid is a liquid, gas, or other material that may continuously motion, move and Deformation (physics), deform (''flow'') under an applied shear stress, or external force. They have zero shear modulus, or, in simpler terms, are M ...
, and
electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...
balance, and systemic vascular resistance. When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin (already present in the blood) into renin and secrete it directly into the circulation. Plasma renin then carries out the conversion of angiotensinogen, released by the liver, to angiotensin I, which has no biological function on its own. Angiotensin I is subsequently converted to the active
angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...
by the
angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...
(ACE) found on the surface of vascular endothelial cells, predominantly those of the
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
s. Angiotensin II has a short life of about 1 to 2 minutes. Then, it is rapidly degraded into angiotensin III by angiotensinases which are present in red blood cells and vascular beds in many tissues. Angiotensin III increases blood pressure and stimulates aldosterone secretion from the adrenal cortex; it has 100% adrenocortical stimulating activity and 40% vasopressor activity of angiotensin II. Angiotensin IV also has adrenocortical and vasopressor activities. Angiotensin II is a potent vasoconstrictive peptide that causes blood vessels to narrow, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the renal tubules to increase the reabsorption of
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
which in consequence causes the reabsorption of water into the blood, while at the same time causing the excretion of
potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
(to maintain
electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...
balance). This increases the volume of extracellular fluid in the body, which also increases blood pressure. If the RAS is abnormally active, blood pressure will be too high. There are several types of drugs which include ACE inhibitors, angiotensin II receptor blockers (ARBs), and renin inhibitors that interrupt different steps in this system to improve blood pressure. These drugs are one of the primary ways to control
high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...
,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
,
kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
, and harmful effects of
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
.


Activation

The system can be activated when there is a loss of
blood volume Blood volume (volemia) is the volume of blood ( blood cells and plasma) in the circulatory system of any individual. Humans A typical adult has a blood volume of approximately 5 liters, with females and males having approximately the same blood p ...
or a drop in
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
(such as in
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...
or
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
). This loss of pressure is interpreted by
baroreceptor Baroreceptors (or archaically, pressoreceptors) are stretch receptors that sense blood pressure. Thus, increases in the pressure of blood vessel triggers increased action potential generation rates and provides information to the central nervous s ...
s in the
carotid sinus In human anatomy, the carotid sinus is a dilated area at the base of the internal carotid artery just superior to the bifurcation of the internal carotid and external carotid at the level of the superior border of thyroid cartilage. The carot ...
. It can also be activated by a decrease in the filtrate
sodium chloride Sodium chloride , commonly known as Salt#Edible salt, edible salt, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is transparent or translucent, brittle, hygroscopic, and occurs a ...
(NaCl) concentration or a decreased filtrate flow rate that will stimulate the macula densa to signal the juxtaglomerular cells to release renin. # If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
renin. # Renin cleaves a
decapeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...
from angiotensinogen, a globular protein. The decapeptide is known as angiotensin I. # Angiotensin I is then converted to an octapeptide, ''
angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...
'' by
angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...
(ACE), which is thought to be found mainly in endothelial cells of the
capillaries A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the in ...
throughout the body, within the lungs and the epithelial cells of the kidneys. One study in 1992 found ACE in all blood vessel endothelial cells. # Angiotensin II is the major bioactive product of the renin–angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them; and to receptors on the zona glomerulosa cells, causing the release of aldosterone from the
zona glomerulosa The ''zona glomerulosa'' (sometimes, glomerular zone) of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches (''glomus'' is Latin ...
in the adrenal cortex. Angiotensin II acts as an
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
,
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...
/
paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...
, and
intracrine Intracrine signaling is a mode of hormone and growth factor action in which signaling molecules exert their effects within the same cell that produces them, without being secreted into the extracellular environment. The term intracrine was origin ...
hormone.


Cardiovascular effects

Angiotensin I may have some minor activity, but angiotensin II is the major bioactive product. Angiotensin II has a variety of effects on the body: * Throughout the body, angiotensin II is a potent vasoconstrictor of
arteriole An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillary, capillaries. Arterioles have vascular smooth muscle, muscular walls (usually only one to two layers of smoo ...
s. * In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on efferent arterioles than afferent. As with most other capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance, raising systemic
arterial blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
and decreasing the blood flow. However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. The
glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearance (medicine), clearing toxins; absorption of glucose, amino acids, and other small molecules; reg ...
(GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow. Because the filtration fraction, which is the ratio of the glomerular filtration rate (GFR) to the renal plasma flow (RPF), has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased
hydrostatic pressure Hydrostatics is the branch of fluid mechanics that studies fluids at hydrostatic equilibrium and "the pressure in a fluid or exerted by a fluid on an immersed body". The word "hydrostatics" is sometimes used to refer specifically to water and o ...
and increased
oncotic pressure Oncotic pressure, or colloid osmotic-pressure, is a type of osmotic pressure induced by the plasma proteins, notably albumin, in a blood vessel's plasma (or any other body fluid such as blood and lymph) that causes a pull on fluid back into ...
(due to unfiltered plasma proteins) in the peritubular capillaries. The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid. * Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the washout of NaCl and
urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...
in the kidney medullary space. Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of the
Loop of Henle In the kidney, the loop of Henle () (or Henle's loop, Henle loop, nephron loop or its Latin counterpart ''ansa nephroni'') is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after it ...
. * Angiotensin II stimulates exchangers located on the apical membranes (faces the tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in addition to channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption. * Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption. * In the adrenal cortex, angiotensin II acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the
distal convoluted tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lum ...
s and the cortical
collecting duct The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct participates in electrolyte and fluid balance through rea ...
s) in the kidneys, causing them to reabsorb more
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood,
potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
is secreted into the tubules, becomes part of urine and is excreted. * Angiotensin II causes the release of anti-diuretic hormone (ADH), also called
vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
– ADH is made in the hypothalamus and released from the posterior
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys. ADH also acts on the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
to increase an individual's appetite for salt, and to stimulate the sensation of
thirst Thirst is the craving for potable 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 or an increase in the concentration of certain osmolites, suc ...
. These effects directly act together to increase blood pressure and are opposed by atrial natriuretic peptide (ANP).


Local renin–angiotensin systems

Locally expressed renin–angiotensin systems have been found in a number of tissues, including the
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s,
adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
s, the
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
,
vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...
and
nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin–angiotensin system, as well as non-cardiovascular functions. Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as precursor to renin is still unclear. Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressed
angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...
, chymase or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial. In the adrenal glands, it is likely involved in the
paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...
regulation of aldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and
peripheral A peripheral device, or simply peripheral, is an auxiliary hardware device that a computer uses to transfer information externally. A peripheral is a hardware component that is accessible to and controlled by a computer but is not a core compo ...
nervous systems can use angiotensin for sympathetic neurotransmission. Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.


Fetal renin–angiotensin system

In the
fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
, the renin–angiotensin system is predominantly a sodium-losing system, as angiotensin II has little or no effect on aldosterone levels. Renin levels are high in the fetus, while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood flow, preventing ACE (found predominantly in the pulmonary circulation) from having its maximum effect.


Clinical significance

* Inhibitors of angiotensin-converting enzyme are often used to reduce the formation of the more potent angiotensin II.
Captopril Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inh ...
is an example of an ACE inhibitor. ACE cleaves a number of other peptides, and in this capacity is an important regulator of the
kinin–kallikrein system The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its importan ...
, as such blocking ACE can lead to side effects. *
Angiotensin II receptor antagonist Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...
s, also known as angiotensin receptor blockers, can be used to prevent angiotensin II from acting on its receptors. * Direct renin inhibitors can also be used for hypertension. The drugs that inhibit renin are aliskiren and the investigational remikiren. *
Vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifi ...
s against angiotensin II, for example CYT006-AngQb, have been investigated.


See also

* Discovery and development of angiotensin receptor blockers * Atrial natriuretic peptide: When the atrium stretches, blood pressure is considered to be increased and sodium is excreted to lower blood pressure. * Bainbridge reflex: In response to stretching of the right atrium wall, heart rate increases, lowering venous blood pressure. * Baroreflex: When the stretch receptors in the aortic arch and carotid sinus increase, the blood pressure is considered to be elevated and the heart rate decreases to lower blood pressure. *
Antidiuretic hormone Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
: The hypothalamus detects the extracellular fluid hyperosmolality and the posterior pituitary gland secretes antidiuretic hormone to increase water reabsorption in the collecting duct.


References


Further reading

*


External links

* {{DEFAULTSORT:Renin-Angiotensin System Biochemical reactions Cardiovascular physiology Endocrinology Human homeostasis