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 a decapeptide called
angiotensin I.[4] Angiotensin I is subsequently converted to
angiotensin II (an octapeptide) by the
angiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly those of the
lungs.[5] Angiotensin II has a short life of about 1 to 2 minutes. Then, it is rapidly degraded into a heptapeptide called
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.[6] Angiotensin II also stimulates the secretion of the hormone
aldosterone[6] from the
adrenal cortex. Aldosterone causes the
renal tubules to increase the reabsorption of
sodium which in consequence causes the reabsorption of water into the blood, while at the same time causing the excretion of
potassium (to maintain
electrolyte balance). This increases the volume of
extracellular fluid in the body, which also increases blood pressure.
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
enzymerenin.
Angiotensin I is then converted to an
octapeptide, angiotensin II by
angiotensin-converting enzyme (ACE),[9] which is thought to be found mainly in endothelial cells of the
capillaries 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.[10]
Angiotensin I may have some minor activity, but angiotensin II is the major bio-active product. Angiotensin II has a variety of effects on the body:[citation needed]
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
systemicarterial blood pressure 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 (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 and increased
oncotic pressure (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 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.
Angiotensin II stimulates Na+ /H+ 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 Na+ 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 tubules and the
corticalcollecting ducts) in the kidneys, causing them to reabsorb more
sodium and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood,
potassium is secreted into the tubules, becomes part of urine and is excreted.
Angiotensin II causes the release of anti-diuretic hormone (ADH),[6] also called
vasopressin – ADH is made in the hypothalamus and released from the posterior
pituitary gland. 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 to increase an individual's appetite for salt, and to stimulate the sensation of
thirst.
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
kidneys,
adrenal glands, the
heart,
vasculature and
nervous system, 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.[9][11][12] 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.[13] 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,
chymase or other enzymes can transform it into angiotensin II.[13][14][15] This process can be intracellular or interstitial.[9]
In the adrenal glands, it is likely involved in the
paracrine regulation of
aldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the
brain, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation.[9][12][16] In addition, both the
central and
peripheral nervous systems can use angiotensin for sympathetic neurotransmission.[17] 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.[9]
Fetal renin–angiotensin system
In the
fetus, the renin–angiotensin system is predominantly a sodium-losing system,[citation needed] 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.[citation needed]
Clinical significance
ACE inhibitors of angiotensin-converting enzyme inhibitors are often used to reduce the formation of the more potent angiotensin II.
Captopril 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, as such blocking ACE can lead to side effects.[18]
^Rogerson FM, Chai SY, Schlawe I, Murray WK, Marley PD, Mendelsohn FA (July 1992). "Presence of angiotensin converting enzyme in the adventitia of large blood vessels". J. Hypertens. 10 (7): 615–620.
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^Kumar R, Singh VP, Baker KM (March 2008). "The intracellular renin-angiotensin system: implications in cardiovascular remodeling". Current Opinion in Nephrology and Hypertension. 17 (2): 168–173.
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^McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, et al. (June 2003). "The brain renin-angiotensin system: location and physiological roles". The International Journal of Biochemistry & Cell Biology. 35 (6): 901–918.
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^Patil J, Heiniger E, Schaffner T, Mühlemann O, Imboden H (April 2008). "Angiotensinergic neurons in sympathetic coeliac ganglia innervating rat and human mesenteric resistance blood vessels". Regulatory Peptides. 147 (1–3): 82–87.
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^Richter WF, Whitby BR, Chou RC (1996). "Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals". Xenobiotica. 26 (3): 243–254.
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^Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, et al. (March 2008). "Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study". Lancet. 371 (9615): 821–827.
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^Brown MJ (October 2009). "Success and failure of vaccines against renin-angiotensin system components". Nature Reviews. Cardiology. 6 (10): 639–647.
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Further reading
Banic A, Sigurdsson GH, Wheatley AM (1993). "Influence of age on the cardiovascular response during graded haemorrhage in anaesthetized rats". Res Exp Med (Berl). 193 (5): 315–321.
doi:
10.1007/BF02576239.
PMID8278677.
S2CID37700794.