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The the renin-angiotensin system (RAS) consists of: active renin,
angiotensin I (AI), angiotensin II (AII) and angiotensin converting
enzyme (ACE), which converts inactive AI into active AII. AII is one
of the most potent vasoconstrictors known, and it also regulates the
secretion of aldosterone, which in turn regulates the excretion of
potassium and the resorption of sodium by the kidneys.
RAS is a defence mechanism to prevent a fall in blood pressure due to
the loss of blood or fluid. However, it can also become activated
inappropriately in pathological conditions, thus resulting in
hypertension. It is activated in states of clinical shock, in cases of
fluid loss through diarrhea or overuse of diuretics, and in conditions
of edema arising from liver or kidney disease or from other causes. If
the renal artery becomes blocked, causing the blood pressure within
the kidney to rise, this will also serve to activate RAS. Increased
production of aldosterone will also activate RAS.
Renin was first discovered in 1898 by Tigerstedt and Bergman, who
found that extracts from the cortex of rabbit kidneys contain a
vasopressor (substance which increases blood pressure). It is an
enzyme. Its structure is a a single-chained, glycosylated carboxy
peptidase, and it belongs to the class of aspartyl proteases. It is
produced in the juxtaglomerular cells of the kidney, which are found
in the afferent arteriole normally close to the entry into the renal
corpuscle. The first product obtained when the renin mRNA is
transcribed is called preprorenin. As this molecule moves to the
endoplasmic reticulum, a peptide made up of 20 amino acids is removed
and the remaining molecule is glycosylated. This gives the inactive
renin precursor called prorenin. It is then moved to the Golgi
apparatus, where it is packed into granules. Within these granules,
prorenin is processed into active renin by the action of a thiol
protease enzyme that removes another 42 amino acids from the molecule
in order to expose the active site. These mature granules will then
secrete renin in a regulated manner.
Renin secretion is stimulated by the following signals:
1. Lowered blood perfusion pressure. This is recognised by
baroreceptors in the kidney. It has been suggested that the
baroreceptors are stretch-sensitive cells in the wall of the afferent
arteriole. (This means that if the blood pressure is increased only
locally in the kidney, it will still stimulate the RAS through this
effect on baroreceptors).
2. Decreased levels of salt in the body. Decreased levels of NaCl in
the urine stimulate the secretion of renin, while increased levels
inhibit secretion. The location in which this is recognised is the
macula densa segment of the glomerulus, and it is suggested that the
mechanism is based on the transport rate of NaCl across the apical
membrane of the macula densa cells.
3. Activation of the sympathetic nervous system. The juxtaglomerular
cells have beta-receptors on their surfaces, which are stimulated by
norepinephrine, which is the transmitter molecule produced at the
terminals of the sympathetic nerves.
4. Local and circulating substances that increase levels of cyclic AMP
stimulate renin release. These include beta-agonists and
prostaglandins.
Renin itself does not have any effects on blood pressure. It acts on
an alpha2-globulin produced by the liver, called angiotensinogen,
which circulates within the plasma. Renin cleaves this molecule to
produce AI, which is a decapeptide. AI is inactive. In order to get
the active AII, two more peptides have to be removed. This is done by
angiotensin converting enzyme, ACE. ACE is found in the walls of
blood capillaries. Most of the conversion takes place within the
blood capillaries of the lungs.
AII is a very potent vasoconstrictor and this in itself causes it to
raise the blood pressure. In this respect, it is about forty times
more potent than norepinephrine. However, it also raises blood
pressure through a second mechanims. It acts on the adrenal gland,
and causes it to release aldosterone. The effect of aldosterone is to
cause the kidney to resorb more sodium and water when processing the
urine. The result is an increase in plasma volume, which again raises
the pressure within the blood vessels. AII also raises blood pressure
by two other mechanisms: it stimulates the cardiovascular center of
the medulla to increase the cardiac output, and it stimulates the
hypothalamus to increase thirst and secretion of antidiuretic hormone
(ADH). The effect of ADH is to cause the kidneys to resorb even more
water, while at the same time water intake will be increased through
drinking, thus leading to a further increase in plasma volume.
However, as the blood pressure rises, there now begins a process of
feedback inhibition. The rise in blood pressure and the increase in
NaCl levels in the urine will act to inhibit the secretion of renin by
the kidney. AII also has a direct effect on the kidney baroreceptors,
causing them to become more sensitive, which causes a further
inhibition of renin secretion. The inhibition of renin secretion
means that no further AI will be produced, and therefore no further
AII. At the same time, the existing AII is inactivated by another
enzyme called angiotensinase.
These two opposing sets of mechanisms act to keep blood pressure
within normal limits, except in certain pathological conditions which
affect the integrity of the RAS. These include local renovascular
hypertension (for example due to blockage of the renal artery),
oversecretion of aldosterone (for example in cases of adrenal tumors),
renin-secreting tumors.
Sources consulted:
http://www.lifeclinic.com/focus/blood/articleView.asp?MessageID=248
(Life Clinic article “How blood pressure is regulated” By: Thomas
Pickering, MD, DPhil, FRCP, Director of Integrative and Behavioral
Cardiology Program of the Cardiovascular Institute at Mount Sinai
School of Medicine, New York.)
http://www.aruplab.com/guides/clt/tests/clt_163b.htm (Arup Labs guide
to clinical assays)
http://www.uninet.edu/cin2000/conferences/OleS/OleS.html (CELLULAR
AND RENAL CONTROL OF RENIN SECRETION by Ole Skøtt and Boye L. Jensen,
Physiology and Pharmacology, University of Southern Denmark, Odense,
Denmark (presented at the First National Conference of Nephrology in
Internet) – includes a VERY detailed discussion of molecular
mechanisms )
http://www.users.globalnet.co.uk/~sandp/Phenotype/Agt/Poly.htm
(Hypertension resource database)
http://wizard.pharm.wayne.edu/biochem/prot.html (Protein structure and
function, by Patrick M. Woster, Wayne State University)
http://members.aol.com/Bio50/LecNotes/lecnot38.html (Regulation of
Salt and Water, by Frank Orme)
Search strategy: 1. renin produced 2. renin structure 3. prorenin
4. angiotensin 5. angiotensinogen |
