Renin-Angiotensin-Aldosterone System - Podcast Version TeachMePhysiology 0:00 / 0:00 1x 0.25x 0.5x 0.75x 1x 1.25x 1.5x 1.75x 2x The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system that is essential for the regulation of blood pressure and fluid balance. The system is mainly comprised of three hormones (renin, angiotensin II, and aldosterone) and is primarily activated in response to reduced renal perfusion. It functions to restore circulating volume and arterial pressure. This article describes the system itself, how it is regulated, and some clinically relevant points surrounding it. Pro Feature - 3D Model You've Discovered a Pro Feature Access our 3D Model Library Explore, cut, dissect, annotate and manipulate our 3D models to visualise anatomy in a dynamic, interactive way. Learn More Overview of RAAS Hormones Renin – Release and Function Renin is released from granular cells of the renal juxtaglomerular apparatus (JGA) in response to one of three factors: Reduced perfusion pressure in the kidney – detected by baroreceptors in the afferent arteriole Reduced sodium delivery to the distal convoluted tubule (DCT) – detected by macula densa cells Sympathetic stimulation of the JGA – via β1 adrenoreceptors The release of renin is inhibited by atrial natriuretic peptide (ANP). When blood pressure increases, the cardiac atria stretches during filling leading to ANP release from atrial cells. Circulating renin cleaves angiotensinogen, a precursor protein produced in the liver, to form angiotensin I. By OpenStax College [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons Fig 1The juxtaglomerular apparatus demonstrated as a diagram, accompanied by an electron micrograph of it in situ Angiotensin II – Production and Function Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE). This mainly occurs in the lungs where ACE is found on the surface of vascular endothelial cells, although ACE is also generated in smaller quantities within the renal endothelium. Angiotensin II exerts its action by binding to various receptors throughout the body. It binds to one of two G-protein coupled receptors (AT1 and AT2 receptors) with most action mediated via the AT1 receptor. The table below outlines its multi-system effects, all aimed at increasing blood pressure. These will be discussed in more detail below. Site Main Action Arterioles Vasoconstriction Kidney Stimulates Na⁺ reabsorption Sympathetic nervous system Increases noradrenaline (NA) release Adrenal cortex Stimulates aldosterone release from zona glomerulosa Hypothalamus Increases thirst sensation and stimulates anti-diuretic hormone (ADH) release Aldosterone – Release and Function Aldosterone is a mineralocorticoid and steroid hormone which acts on the principal cells of the collecting ducts in the nephron. It increases expression of apical epithelial Na⁺ channels (ENaC), promoting urinary sodium reabsorption. The additional sodium reabsorbed through ENaC is pumped into the blood by the Na⁺/K⁺ pump. Thus, potassium from the blood enters the principal cell of the nephron, in exchange for sodium. This potassium exits the cell into the renal tubule to be excreted into the urine, reducing levels of potassium in the blood. Ultimately, aldosterone increases sodium reabsorption allowing for greater fluid retainment and therefore increased intravascular volume and blood pressure whilst potassium is lost in urine. Systemic Effects of Angiotensin II Cardiovascular Effects Angiotensin II is a potent vasoconstrictor. It acts on AT1 receptors in arteriolar endothelium to activate a Gq protein whose signalling cascade increases intracellular calcium causing vasoconstriction. This vasoconstriction increases total peripheral resistance and consequently, blood pressure. Neural and Endocrine Effects Angiotensin II acts at the hypothalamus to stimulate thirst, increasing fluid consumption. Additionally, it increases ADH secretion from the posterior pituitary gland , which increases renal reabsorption of water, resulting in excretion of concentrated urine. Together, this increases the circulating volume and blood pressure. Further information on ADH can be found here. Angiotensin II also stimulates the sympathetic nervous system to increase noradrenaline (NA) release. Though typically involved in the fight or flight response, NA has a variety of actions that are relevant to the RAAS. It increases cardiac output, vasoconstricts arterioles and increases renin release. Renal Effects Angiotensin II acts on the kidneys to preserve glomerular filtration and increase sodium reabsorption through mechanisms summarised in the table below: Target Action Mechanism Renal artery and afferent arteriole Vasoconstriction Via AT1 receptor, activates Gq protein opening voltage-gated calcium channels causing Ca⁺ influx Efferent arteriole Vasoconstriction (greater than the afferent arteriole) Mesangial cells Contraction, leading to a decreased filtration area and reduced GFR Proximal convoluted tubule Increased Na⁺ reabsorption Increased Na⁺/H⁺ antiporter activity Adjusts Starling forces in peritubular capillaries, increasing paracellular reabsorption Collecting Ducts Increased water reabsoprtion Indirectly, via ADH which increases expression of aquaporin-2 channels Tubuloglomerular feedback The release of renin from the JGA in response to low sodium delivery to the DCT ultimately increasing renal perfusion, GFR and sodium delivery to the DCT is a form of negative feedback. The opposite occurs in high sodium delivery, where release of adenosine causes afferent arteriolar vasoconstriction to reduce GFR and sodium delivery to the DCT. This feedback mechanism ensures the GFR and therefore sodium and water delivery to the tubules is finely balanced with the reabsorption capacity of the nephron. Angiotensin II independently increases the sensitivity of the tubuloglomerular feedback mechanism, both to the preferential vasoconstriction of the efferent arteriole by the RAAS and the vasoconstriction of the afferent arteriole by adenosine. Thus, angiotensin II is important in both arms of this feedback loop. In the context of potentiating the effects of the RAAS, vasoconstriction of both afferent and efferent arteriole are exaggerated which reduces renal blood flow and GFR. This allows the nephrons time to reabsorb more of the filtrate, producing a low volume, concentrated urine. Soupvector, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia CommonsFig 2Diagram outlining the RAAS and its actions on the body. 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 reducing the levels of angiotensin II within the body. This effectively reduces the activity of the RAAS causing the following physiological effects: Decreased arteriolar vasoconstriction and resistance Reduced aldosterone secretion, resulting in decreased sodium and water retention Reduced preload and afterload, improving cardiac efficiency in heart failure Reduced potassium excretion in the kidneys These actions lower blood pressure in hypertensive patients and improve outcomes in patients with heart failure. Typical side effects include dry cough, hyperkalaemia, headache, dizziness, fatigue, renal impairment, and rarely, angioedema. Clinical Relevance Renal Disease The two most important prognostic factors in chronic kidney disease are hypertension and proteinuria. ACE inhibitors are therefore important in the management of diabetic nephropathy and other forms of chronic renal impairment as they reduce both systemic blood pressure and urinary protein excretion. The reduction in proteinuria is thought to be due to the preferential vasoconstriction of the efferent arteriole in the glomerulus. This lowers intraglomerular pressure, reducing the leakage of protein into the urine. ACE inhibitors must be used with caution in patients with bilateral renal artery stenosis and are often withheld in acute kidney injury, as the reduction in GFR can be pronounced and harmful. Clinical Relevance Hyperaldosteronism Hyperaldosteronism refers to the excess production of aldosterone by the adrenal glands. It is associated with increased sodium and water reabsorption, causing hypertension and hypokalaemia. It can be classified as primary (from within the adrenal glands) or secondary (excess aldosterone due to processes originating outside the adrenal glands). Primary hyperaldosteronism Secondary hyperaldosteronism Pathology Overactive adrenal glands Reduced renal perfusion Renin Suppressed due to hypertension Increased in response to poor renal perfusion Aldosterone Produced by adrenals in excess causing hypertension Produced in excess in response to renin Causes Bilateral adrenal hyperplasia (most common) Conn’s syndrome (aldosterone-producing adrenal adenoma) Familial hyperaldosteronism (least common) Renal artery stenosis Heart failure Liver cirrhosis Management may involve use of aldosterone antagonists e.g. eplerenone or spironolactone. Surgical methods can address underlying causes such as removal of adrenal tumours or renal artery angioplasty. Do you think you’re ready? 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