Hormonal Regulation

The Renin-Angiotensin-Aldosterone-System

The renin-angiotensin-aldosterone-system, or RAAS for short, is a complex hormonal regulator of blood volume and pressure which influences cardiac output and arterial pressure. Many endocrine hormones are involved in the RAAS, illustrated in figure 1. This system proceeds through several steps to produce angiotensin II, which acts to stabilize blood pressure and volume. As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone.

Renin is secreted by a part of the juxtaglomerular complex and is produced by the granular cells of the afferent and efferent arterioles. Thus, the kidneys control blood pressure and volume directly. Renin acts on angiotensinogen, which is made in the liver and converts it to angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and as a result of this, raises blood pressure. It also triggers the release of aldosterone from the adrenal cortex, which in turn stimulates the renal tubules to reabsorb more sodium. Angiotensin II also triggers the release of antidiuretic hormone (ADH) from the hypothalamus, leading to water retention in the kidneys. It acts directly on the nephrons and decreases the glomerular filtration rate. ^[1]

Angiotensin II is a potent vasoconstrictor that is involved in maintaining homeostatic blood pressure. Its release is stimulated by decreases in blood pressure and it acts to return blood pressure to normal levels. It acts systemically to cause both vasoconstriction and venoconstriction, ultimately leading to the desired increase in blood pressure. But how does it act on the kidney?

Angiotensin II constricts both the afferent and efferent arterioles of the glomerulus. This reduces both glomerular filtration rate and renal blood flow, thereby limiting urine output and preserving blood volume. Its other direct effect on the kidney involves increasing sodium and water retention. Angiotensin II also stimulates the adrenal cortex to release aldosterone, which in turn acts on the kidneys to further increase sodium and fluid retention. In addition, angiotensin II stimulates the release of antidiuretic hormone (ADH) from the posterior pituitary which also causes an increase in sodium and fluid retention by the kidneys. Thirst centers within the brain are activated and this facilitates norepinephrine release from the sympathetic nerve endings and inhibits norepinephrine reuptake by nerve endings. The sympathetic adrenergic function is enhanced and in the end, this stimulates both cardiac hypertrophy and vascular hypertrophy. Figure 2, shown below, is a helpful tool to visualize the effects of angiotensin II on the body. ^[3]

Aldosterone

Aldosterone (ALDO) is released from the adrenal cortex in response to an increase in angiotensin II. Aldosterone release stimulates increased reabsorption of sodium and given that water follows sodium, this results in an increased reabsorption of water. This overall increase in fluid retention leads to an increase in blood pressure. Did you know that progesterone is structurally very similar to aldosterone? Because of this, progesterone is able to bind to aldosterone receptors stimulating sodium and fluid retention. This could explain the increase in fluid retention that occurs in menstruators during parts of their menstrual cycle in which progesterone levels are high. The following video is a useful summary of the RAAS. While it is not a fully fleshed explanation, it may help if you are struggling with the foundation of this system. ^{[4] [5]}

Angiotensin-Converting Enzyme

While angiotensin-converting enzyme (ACE) is not a hormone, it is incredibly important in the regulation of kidney function and therefore, blood pressure. ACE is an enzyme that is produced in the lungs and released into the systemic circulation. There, it finds its way to the kidney and binds to the surface of the afferent arteriole and glomerular endothelium. This is where it will convert angiotensin I into angiotensin II, which then goes on to promote an increase in blood pressure. ^[6]

Antidiuretic Hormone

Have you ever wondered why you feel dehydrated after having a few glasses of wine or beer? This is because alcohol is a diuretic that inhibits the release of antidiuretic hormone (ADH). This hormone is produced in the hypothalamus and is delivered to the posterior pituitary for storage and release. ADH controls the amount of water reabsorbed from the collecting ducts and tubules in the kidney. When osmoreceptors in the hypothalamus detect an increase in the concentration of blood plasma, the hypothalamus signals the release of ADH from the posterior pituitary into the bloodstream. ADH will also be released if the low-pressure baroreceptors in the body detect a decrease in blood volume or pressure. This will decrease the inhibition of ADH secreting cells in the posterior pituitary and promote its release. ADH acts on the body by changing the permeability of the nephron to water and causing systemic vasoconstrictor, as described in the following paragraphs.

ADH alters the permeability of the nephrons by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts. This results in an increase in the water permeability of these cells and, thus, a large increase in water passage from the urine through the walls of the collecting tubules, leading to more reabsorption of water into the bloodstream. When the blood plasma becomes less concentrated and the level of ADH decreases, aquaporins are removed from collecting tubule cell membranes, and the passage of water out of urine and into the blood decreases. The video below explains the movement of aquaporins to the apical side of the membrane in the collecting duct.

Did you know that antidiuretic hormone (ADH) is also called vasopressin? Early researchers found that in cases of unusually high secretion of ADH, the hormone caused vasoconstriction or vasopressor activity, hence the name. ADH causes the vasoconstriction of the afferent arterioles in the peripheral circulation reducing the flow of blood to the extremities and thereby increasing the blood supply to the core of the body. Only later were its antidiuretic properties identified. Synthetic ADH is still used occasionally to stem life-threatening esophagus bleeding in alcoholics due to its vasoconstrictive actions. ^{[7] [8]}

Natriuretic Hormones

Natriuretic hormones are a peptide hormone group that counter the effects of the RAAS, acting to lower blood pressure. You may remember one natriuretic hormone in particular from your course notes, the atrial natriuretic peptide, or ANP. ANP is produced by the atria of the heart in response to the stimulus of the stretch receptors; which could be caused by an increase in blood pressure or volume. ANP and other members of this hormone group act to inhibit the release of aldosterone. Remember, aldosterone acts on the kidney to increase salt and fluid retention. Therefore, inhibiting its release would force sodium to remain in the filtrate and since water passively follows sodium, this will also increase fluid loss and an overall decrease in blood volume and pressure. In addition, ANP acts as a vasodilator on the afferent arteriole of the glomerulus while it vasoconstricts the efferent arteriole. This in turn increases glomerular filtration rate, leading to an increase in sodium and fluid lost in the urine. Finally, ANP acts to decrease the reabsorption of sodium in the distal convoluted tubule of the nephron. The flowchart in figure 3 is helpful in visualizing how ANP directly impedes the RAAS.

As you can see in the image above, ANP also inhibits the release of renin and antidiuretic hormone (ADH). By inhibiting the release of renin, it further interrupts the RAAS by preventing the activation of the system itself. In addition, by inhibiting the release of antidiuretic hormone, it further promotes diuresis by decreasing the nephron’s permeability to water preventing its reabsorption. ^[9]

 

Tips From Past Students

Remember: All of the effects of ANP will work to increase filtration and decrease reabsorption at the kidney. This will lead to an increase in the excretion of water which will decrease blood volume and blood pressure.

 

Did you know that there is also a B-type natriuretic peptide? This is abbreviated as BNP and it is produced in the ventricles of the heart. BNP is much less potent than ANP since its receptor affinity is lower. Since its effects are minute, it is theorized that BNP is useful in small tweaks in blood pressure regulation. ^[10]

This table summarizes the hormones that have been discussed thus far. This is helpful in understanding the mechanisms of the kidney and may be helpful to refer back to as you study. ^[11]

 

Subchapter Quiz

The questions below can be used to assess your knowledge within this chapter. There are multiple-choice questions that you should attempt without referring to your notes. The questions will provide you with responses to your answers to guide your studying but should not be used as your only resource.