Physiology, Renin Angiotensin System

John H. Fountain; Sarah L. Lappin.

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Last Update: May 5, 2019.

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Introduction
The renin–angiotensin–aldosterone system (RAAS) is a critical regulator of blood volume and
systemic vascular resistance. While the baroreceptor reflex responds in a short-term manner to
decreased arterial pressure, the RAAS is responsible for more chronic alterations. It is composed
of three major compounds: renin, angiotensin II, and aldosterone. These three act to elevate
arterial pressure in response to decreased renal blood pressure, decreased salt delivery to the
distal convoluted tubule, and/or beta-agonism. Through these mechanisms, the body can elevate
the blood pressure in a prolonged manner.[1][2][3]
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Organ Systems Involved

Function
The RAAS functions to elevate blood volume and arterial tone in a prolonged manner. It does
this by increasing sodium reabsorption, water reabsorption, and vascular tone.

Mechanism
Within the afferent arterioles of the kidney, specialized cells called juxtaglomerular (JG) cells
contain prorenin. While prorenin is secreted constitutively in its inactive form, activation of JG
cells causes the cleavage of prorenin to renin. Activation of these cells occurs in response to
decreased blood pressure, beta-activation, or activation by macula densa cells in response to a
decreased sodium load in the distal convoluted tubule.[4][5]
Once renin has been released into the blood, it can act on its target, angiotensinogen.
Angiotensinogen is produced in the liver and is found continuously circulating in the plasma.
Renin then acts to cleave angiotensinogen into angiotensin I. Angiotensin I is physiologically
inactive, but acts as a precursor for angiotensin II.
The conversion of angiotensin I to angiotensin II is catalyzed by an enzyme called angiotensin
converting enzyme (ACE). ACE is found primarily in the vascular endothelium of the lungs and
kidneys. After angiotensin I is converted to angiotensin II, it has effects on the kidney, adrenal
cortex, arterioles, and brain by binding to angiotensin II type I (AT) and type II (AT) receptors.
The effects discussed below are a result of binding to AT receptors. The role of AT receptors is
still being investigated, but pertinently, they have been shown to cause vasodilation by nitric
oxide generation. In the plasma, angiotensin II has a half-life of 1-2 minutes, at which point
peptidases degrade it into angiotensin III and IV. Angiotensin III has been shown to have 100%
of the aldosterone stimulating effect of angiotensin II, but 40% of the pressor effects, while
angiotensin IV has further decreased the systemic effect.
In the proximal convoluted tubule of the kidney, angiotensin II acts to increase Na-H exchange,
increasing sodium reabsorption. Increased levels of Na in the body acts to increase the
osmolarity of the blood, leading to a shift of fluid into the blood volume and extracellular space
(ECF). This increases the arterial pressure of the patient.
Angiotensin II also acts on the adrenal cortex, specifically the zona glomerulosa. Here, it
stimulates the release of aldosterone. Aldosterone is a steroid hormone that causes an increase in
sodium reabsorption and potassium excretion at the distal tubule and collecting duct of the
nephron. Aldosterone works by stimulating the insertion of luminal Na channels and basolateral
Na-K ATPase proteins. The net effect is an increased level of sodium reabsorption. This has the
same effect as mentioned previously: the increased total body sodium leads to an increase in
osmolarity and subsequent increase in blood and ECF volume. In contrast to angiotensin II,
aldosterone is a steroid hormone. As a result, it enacts change by binding to nuclear receptors
and altering gene transcription. Thus, the effects of aldosterone may take hours to days to begin,
while the effects of angiotensin II are rapid.
The effect of angiotensin II on vasoconstriction takes place in systemic arterioles. Here,
angiotensin II binds to G protein-coupled receptors, leading to a secondary messenger cascade
that results in potent arteriolar vasoconstriction. This acts to increase total peripheral resistance,
causing an increase in blood pressure.
Finally, angiotensin II acts on the brain. Here, it has three effects. First, it binds to the
hypothalamus, stimulating thirst and increased water intake. Second, it stimulates the release of
antidiuretic hormone (ADH) by the posterior pituitary. ADH, or vasopressin, acts to increase
water reabsorption in the kidney by inserting aquaporin channels at the collecting duct. Finally,
angiotensin II decreases the sensitivity of the baroreceptor reflex. This diminishes baroreceptor
response to an increase in blood pressure, which would be counterproductive to the goal of the
RAAS.
The net effect of these interactions is an increase in total body sodium, total body water, and
vascular tone.
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Clinical Significance
The RAAS acts to manage blood volume and arteriolar tone on a long-term basis. While minor
and rapid shifts are typically managed via the baroreceptor reflex, the RAAS can alter blood
volume chronically. Though the RAAS serves a critical function, it can be activated
inappropriately in several conditions that may then lead to the development of hypertension. For
example, renal artery stenosis results in a decreased volume of blood reaching one (or both)
kidneys. As a result, the juxtaglomerular cells will sense a decrease in blood volume, activating
the RAAS. This can lead to an inappropriate elevation of circulating blood volume and arteriolar
tone due to poor renal perfusion.[6][7]
Pharmacologically, the RAAS is a frequently manipulated system in the management of heart
failure, hypertension, diabetes mellitus, and acute myocardial infarction. ACE inhibitors (e.g.,
enalapril), angiotensin receptor blockers (ARBs, e.g., losartan), and aldosterone antagonists (e.g.,
spironolactone) all act to decrease the effect of the RAAS.
The varied mechanisms of these drugs allow their utilization in different scenarios. ACE
inhibitors inhibit the action of angiotensin-converting enzymes, thus decreasing the production of
angiotensin II. ARBs act to block AT receptors, thus inhibiting angiotensin’s effect while
maintaining normal levels of the compound. Aldosterone inhibitors have two specific varieties.
The first (e.g., spironolactone or eplerenone) act as aldosterone antagonists. These work by
preventing the binding of aldosterone to binding sites in the kidney, preventing insertion of Na
channels. The second (e.g., amiloride or triamterene) group act to block the inserted Na channels
in the distal convoluted tubule.
A common use for ACE inhibitors or ARBs is in the management of hypertension. In these
cases, blocking or decreasing levels of angiotensin II will lead to a reduction in blood pressure.
They achieve this goal by decreasing sodium and water reabsorption, leading to a reduction in
blood volume, and decreasing arteriolar tone. In addition, these drugs are often used in the
management of diabetes mellitus. Patients with diabetes mellitus often have renal manifestations
such as proteinuria due to excess glucose damaging the glomerulus. Using ACE inhibitors or
ARBs can decrease efferent arteriolar tone, leading to a reduction in pressure on the glomerulus.
Thus, they are frequently used for prevention of worsening diabetic nephropathy.