The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system within the body that is essential for regulation of blood pressure and fluid balance. It is comprised of the three hormones renin, angiotensin II and aldosterone and regulated primarily by renal blood flow.
This article shall discuss the system, how it is regulated and clinically relevant conditions to its dysfunction.
The first stage of the RAAS is release of the enzyme renin. This is released from granular cells of the renal juxtaglomerular apparatus (JGA) in response to one of three factors:
- Reduced NaCl delivery to the distal tubule detected by macula densa cells
- Reduced perfusion pressure in the kidney detected by baroreceptors in the afferent arteriole
- Sympathetic stimulation of the JGA
Production of Angiotensin II
Angiotensinogen is a precursor protein produced in the liver and cleaved by renin to form angiotensin I.
Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE). ACE is found within the renal endothelium, the lungs and capillary endothelium.
Angiotensin II Receptors
Once produced, angiotensin II binds to various receptors throughout the body to exert its action. There are two G-protein coupled receptors that have been identified, AT1 and AT2, although most actions occurs via the AT1 receptor.
|Kidney||Stimulates Na+ reabsorption|
|Sympathetic nervous system||Increased release of noradrenaline (NA)|
|Adrenal cortex||Stimulates release of aldosterone|
|Hypothalamus||Increases thirst sensation and stimulates anti-diuretic hormone (ADH) release|
Effects of Angiotensin II
As shown in the table above angiotensin II exerts its action at various sites throughout the body.
Throughout the body it acts on AT1 receptors found in the endothelium of arterioles to achieve vasoconstriction. This signalling occurs via a Gq protein to activate phospholipase C and subsequently increase intracellular calcium.
This results in an increase in total peripheral resistance and therefore, blood pressure.
Angiotensin II acts on the hypothalamus to stimulate the sensation of thirst, resulting in an increase in fluid consumption. This helps to raise the circulating volume and in turn, blood pressure. It also increases the secretion of ADH from the posterior pituitary gland – resulting in the production of more concentrated urine to reduce the loss of fluid from urination. This allows the circulating volume to be better maintained until more fluids can be consumed.
Further information on ADH can be found here.
It also acts on the sympathetic nervous system to increase the release of NA. This hormone is typically associated with the “fight or flight” response in stressful situations and has a variety of actions that are relevant to the RAAS:
- Increase in cardiac output
- Vasoconstriction of arterioles
- Release of renin
Angiotensin II acts on the kidneys to produce a variety of effects, including afferent and efferent arteriole constriction and increased Na+ reabsorption. These effects and their mechanisms are summarised in the table below.
|Renal artery and afferent arteriole||Vasoconstriction||Voltage-gated calcium channels open and allow an influx of calcium ions|
|Efferent arteriole||Vasoconstriction (greater than the afferent arteriole)||Activation of AT1 receptor|
|Mesangial cells||Contraction, leading to a decreased filtration area||Activation of Gq receptors and opening of voltage-gated calcium channels|
|Proximal tubule||Increased Na+ reabsorption||Increased Na+/H+ antiporter activity and adjustment of the Starling forces in peritubular capillaries to increase paracellular reabsorption|
It also acts as a sensitiser to tubuloglomerular feedback, which helps to prevent an excessive rise in glomerular filtration rate. This is also prevented by the local release of prostaglandins, which have an antagonistic effect to the renal vasoconstriction occurring.
Finally, angiotensin II acts on the adrenal cortex to stimulate the release of aldosterone. This then acts on the principal cells of the collecting ducts in the nephron to stimulate Na+ and water reabsorption. It also increases the expression of apical epithelial Na+ channels (ENaC) and K+ channels. As well as this the activity of the basolateral Na+/K+/ATPase is increased to increase the extrusion of the reabsorbed Na+ from the cells.
Clinical Relevance – ACE Inhibitors
ACE inhibitors are a class of drug typically used in the treatment of hypertension and heart failure. Examples include; ramipril, lisinopril and enalapril.
They inhibit the action of angiotensin converting enzyme and so reduce the levels of angiotensin II within the body. This means that it reduces the activity of the RAAS within the body. The physiological effects of these drugs therefore, include:
- Decreased arteriolar resistance
- Decreased arteriolar vasoconstriction
- Decreased cardiac output
- Increased sodium excretion in the kidneys
These actions help to lower blood pressure in hypertensive patients and also help to improve outcomes in conditions such as heart failure.
Typical side effects include dry cough, hyperkalaemia, headache, dizziness, fatigue, renal impairment and rarely, angioedema.