Reninangiotensin system

Renin-angiotensin-aldosterone system

heart failure, kidney failure, and harmful eects of

diabetes.[4][5]

Hypothalamus of brain
Corticotropin-releasing hormone
Pituitary gland
Thirst
Antidiuretic hormone

1 Activation

+
+
ACTH

Vasoconstriction of
blood vessels

Effective +
circulating
volume
Extracellular
fluid +
volume
Blood +
pressure

Angiotensin II
ACE
in lungs

High plasma K

Liver

Adrenals
Aldosterone
Kidneys

Na+ excretion

H2O excretion +
K excretion +

RAAS schematic

Angiotensinogen

The system can be activated when there is a loss of

blood volume or a drop in blood pressure (such as in
Renin
Angiotensin I
hemorrhage or dehydration). This loss of pressure is interpreted by baroreceptors in the carotid sinus. In alternative fashion, a decrease in the ltrate NaCl concentraAnatomical diagram of RAAS[1]
tion and/or decreased ltrate ow rate will stimulate the
The reninangiotensin system (RAS) or the renin macula densa to signal the juxtaglomerular cells to release
angiotensinaldosterone system (RAAS) is a hormone renin.
system that regulates blood pressure and water (uid) bal1. If the perfusion of the juxtaglomerular apparatus
ance.
in the kidneys macula densa decreases, then the
When renal blood ow is reduced, juxtaglomerular cells
juxtaglomerular cells (granular cells, modied periin the kidneys convert the prorenin already present in
cytes in the glomerular capillary) release the enzyme
the blood into renin and secrete it directly into circurenin.
lation. Plasma renin then carries out the conversion of
[2]
angiotensinogen released by the liver to angiotensin I.
2. Renin cleaves a zymogen, an inactive peptide, called
Angiotensin I is subsequently converted to angiotensin II
angiotensinogen, converting it into angiotensin I.
by the enzyme angiotensin-converting enzyme found in
3. Angiotensin I is then converted to angiotensin II by
the lungs. Angiotensin II is a potent vaso-active pepangiotensin-converting enzyme (ACE),[6] which is
tide that causes blood vessels to constrict, resulting in
thought to be found mainly in lung capillaries. One
increased blood pressure.[3] Angiotensin II also stimu[3]
study in 1992 found ACE in all blood vessel enlates the secretion of the hormone aldosterone from the
dothelial cells.[7]
adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water
4. Angiotensin II is the major bioactive product of the
into the blood. This increases the volume of uid in the
renin-angiotensin system, binding to receptors on
body, which also increases blood pressure.
intraglomerular mesangial cells, causing these cells
to contract along with the blood vessels surrounding
them and causing the release of aldosterone from the
zona glomerulosa in the adrenal cortex. Angiotensin
II acts as an endocrine, autocrine/paracrine, and
intracrine hormone.

If the reninangiotensinaldosterone system is abnormally active, blood pressure will be too high. There are
many drugs that interrupt dierent steps in this system
to lower blood pressure. These drugs are one of the
main ways to control high blood pressure (hypertension),
1

Cardiovascular eects
Further reading: Angiotensin#Eects and
Aldosterone#Function

LOCAL RENIN-ANGIOTENSIN SYSTEMS

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.

It is believed that angiotensin I may have some minor activity, but angiotensin II is the major bio-active product.
Angiotensin II has a variety of eects on the body:
Throughout the body, it is a potent vasoconstrictor
of arterioles.
In the kidneys, AII constricts glomerular arterioles,
having a greater eect on eerent arterioles than
aerent. As with most other capillary beds in the
body, the constriction of aerent arterioles increases
the arteriolar resistance, raising systemic arterial
blood pressure and decreasing the blood ow. However, the kidneys must continue to lter enough
blood despite this drop in blood ow, necessitating
mechanisms to keep glomerular blood pressure up.
To do this, angiotensin II constricts eerent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. The glomerular
ltration rate (GFR) is thus maintained, and blood
ltration can continue despite lowered overall kidney blood ow. Because the ltration fraction has
increased, there is less plasma uid in the downstream peritubular capillaries. This in turn leads to
a decreased hydrostatic pressure and increased oncotic pressure (due to unltered plasma proteins) in
the peritubular capillaries. The eect of decreased
hydrostatic pressure and increased oncotic pressure
in the peritubular capillaries will facilitate increased
reabsorption of tubular uid.
Angiotensin II decreases medullary blood ow
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
uid. Furthermore, increased reabsorption of uid
into the medulla will increase passive reabsorption

In the adrenal cortex, it acts to cause the release

of aldosterone. Aldosterone acts on the tubules
(e.g., the distal convoluted tubules and the cortical
collecting 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.
Release of anti-diuretic hormone (ADH),[3] also
called vasopressin ADH is made in the hypothalamus and released from the posterior pituitary
gland. As its name suggests, it also exhibits vasoconstrictive 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 individuals appetite for salt, and to stimulate the sensation of thirst.
These eects directly act together to increase blood pressure and are opposed by atrial natriuretic peptide (ANP).

3 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.[6][8][9] 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.[10] 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

3
angiotensin II.[10][11][12] This process can be intracellular
or interstitial.[6]
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.[6][9][13] In addition, both the central
and peripheral nervous systems can use angiotensin for
sympathetic neurotransmision.[14] Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system
may aect the expression of those local systems, benecially or adversely.[6]

Fetal renin-angiotensin system

In the fetus, the renin-angiotensin system is predominantly a sodium-losing system, as angiotensin II has little
or no eect on aldosterone levels. Renin levels are high
in the fetus, while angiotensin II levels are signicantly
lower; this is due to the limited pulmonary blood ow,
preventing ACE (found predominantly in the pulmonary
circulation) from having its maximum eect.

Clinical signicance
Inhibitors of angiotensin-converting enzyme (ACE
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 kininkallikrein system, as such
blocking ACE can lead to side eects.
Angiotensin receptor blockers (ARBs) can be used
to prevent angiotensin II from acting on angiotensin
receptors.
Direct renin inhibitors can also be used for
hypertension.[15] The drugs that inhibit renin are
aliskiren[16] and the investigational remikiren.[17]
Vaccines against angiotensin II, for example
CYT006-AngQb, have been investigated.[18][19]

See also
Renin inhibitor
ACE inhibitor
Angiotensin II receptor antagonist
Discovery and development of angiotensin receptor blockers

7 References
[1] Boron, Walter F. (2003). Integration of Salt and
Water Balance (pp. 8667); The Adrenal Gland (p.
1059)". Medical Physiology: A Cellular And Molecular
Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.
[2] Kumar, Abbas; Fausto, Aster (2010). 11. Pathologic
Basis of Disease (8th ed.). Saunders Elsevier. p. 493.
ISBN 978-1-4160-3121-5.
[3] Yee AH, Burns JD, Wijdicks EF (April 2010). Cerebral salt wasting: pathophysiology, diagnosis, and treatment.
Neurosurg Clin N Am 21 (2): 33952.
doi:10.1016/j.nec.2009.10.011. PMID 20380974.
[4] High Blood Pressure: Heart and Blood Vessel Disorders. Merck Manual Home Edition.
[5] Solomon, Scott D; Anavekar, Nagesh (2005). A Brief
Overview of Inhibition of the Renin-Angiotensin System:
Emphasis on Blockade of the Angiotensin II Type-1 Receptor. Medscape Cardiology 9 (2).
[6] Paul M, Poyan Mehr A, Kreutz R (July 2006).
Physiology of local renin-angiotensin systems. Physiol.
Rev. 86 (3): 747803. doi:10.1152/physrev.00036.2005.
PMID 16816138.
[7] 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
20. doi:10.1097/00004872-199207000-00003. PMID
1321187.
[8] Kobori, H.; Nangaku, M.; Navar, L. G.; Nishiyama, A.
(1 September 2007). The Intrarenal Renin-Angiotensin
System: From Physiology to the Pathobiology of Hypertension and Kidney Disease. Pharmacological Reviews
59 (3): 251287. doi:10.1124/pr.59.3.3. PMC 2034302.
PMID 17878513.
[9] Ehrhart-Bornstein, M; Hinson, JP; Bornstein, SR;
Scherbaum, WA; Vinson, GP (April 1998). Intraadrenal
interactions in the regulation of adrenocortical
steroidogenesis.
Endocrine reviews 19 (2): 101
43. doi:10.1210/er.19.2.101. PMID 9570034.
[10] Nguyen, G (March 2011). Renin, (pro)renin and receptor: an update. Clinical science (London, England
: 1979) 120 (5): 16978. doi:10.1042/CS20100432.
PMID 21087212.
[11] 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
doi:10.1097/MNH.0b013e3282f521a8.
PMID
73.
18277150.
[12] Kumar, R; Singh, VP; Baker, KM (April 2009).
The intracellular renin-angiotensin system in the
heart. Current hypertension reports 11 (2): 10410.
doi:10.1007/s11906-009-0020-y. PMID 19278599.

[13] McKinley, MJ; Albiston, AL; Allen, AM; Mathai, ML;

May, CN; McAllen, RM; Oldeld, BJ; Mendelsohn, FA;
Chai, SY (June 2003). The brain renin-angiotensin system: location and physiological roles. The international
journal of biochemistry & cell biology 35 (6): 90118.
doi:10.1016/S1357-2725(02)00306-0. PMID 12676175.
[14] Patil J, Heiniger E, Schaner T, Mhlemann O, Imboden H (April 2008). Angiotensinergic neurons in sympathetic coeliac ganglia innervating rat and human mesenteric resistance blood vessels. Regul. Pept. 147 (1
3): 827. doi:10.1016/j.regpep.2008.01.006. PMID
18308407.
[15] Presentation on Direct Renin Inhibitors as Antihypertensive Drugs
[16] Gradman A, Schmieder R, Lins R, Nussberger J, Chiangs Y, Bedigian M (2005). Aliskiren, a novel orally
eective renin inhibitor, provides dose-dependent antihypertensive ecacy and placebo-like tolerability in
hypertensive patients. Circulation 111 (8): 1012
8. doi:10.1161/01.CIR.0000156466.02908.ED. PMID
15723979.
[17] 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
54. doi:10.3109/00498259609046705. PMID 8730917.
[18] Tissot AC, Maurer P, Nussberger J, Sabat R, Pster T,
Ignatenko S, Volk HD, Stocker H, Mller P, Jennings
GT, Wagner F, Bachmann MF (March 2008). Eect
of immunisation against angiotensin II with CYT006AngQb on ambulatory blood pressure: a double-blind,
randomised, placebo-controlled phase IIa study. Lancet
371 (9615): 8217. doi:10.1016/S0140-6736(08)603815. PMID 18328929.
[19] Brown, MJ (2009).
Success and failure of vaccines against renin-angiotensin system components. Nature reviews. Cardiology 6 (10): 63947.
doi:10.1038/nrcardio.2009.156. PMID 19707182.

Banic A, Sigurdsson GH, Wheatley AM (1993).

Inuence of age on the cardiovascular response
during graded haemorrhage in anaesthetized
rats. Res Exp Med (Berl) 193 (5): 31521.
doi:10.1007/BF02576239. PMID 8278677.

External links
Renin-Angiotensin System at the US National
Library of Medicine Medical Subject Headings
(MeSH)

EXTERNAL LINKS

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