74 Extrinsic control of GFR

Learning Objectives

After reading this section, you should be able to-

  • For the renin-angiotensin system (RAS), describe the factors that initiate renin release, the pathway from angiotensinogen to angiotensin II (ANGII), and the effects of ANGII on various tissues.​
  • Describe the signals that cause release of aldosterone from the adrenal cortex and the effect of aldosterone on the nephron, including the tubule segment involved and the transport mechanisms that are altered by aldosterone.​
  • Describe the effect of vasopressin (ADH, antidiuretic hormone) on the nephron and on the final concentration of urine.​
  • Describe the factors that cause release of natriuretic peptide hormones, their sites of synthesis, and their effects on the nephron. ​
Extrinsic control mechanisms have an effect on GFR, but their primary function is to maintain systemic blood pressure (MAP). While the intrinsic controls function to specifically control GFR at the level of the kidneys, the neural and hormonal controls have a broader scope and function to meet the whole body’s needs, not just those of the kidneys.

Sympathetic nerves

The kidneys are innervated by the sympathetic neurons of the autonomic nervous system via the celiac plexus and splanchnic nerves. Reduction of sympathetic stimulation results in vasodilation and increased blood flow through the kidneys during resting conditions. When the frequency of action potentials increases, the arteriolar smooth muscle constricts (vasoconstriction), resulting in diminished glomerular flow, so that less filtration occurs. Under conditions of stress, sympathetic nervous activity increases, resulting in the direct vasoconstriction of afferent arterioles (norepinephrine effect) as well as stimulation of the adrenal medulla. The adrenal medulla, in turn, produces a generalized vasoconstriction through the release of epinephrine. This includes vasoconstriction of the afferent arterioles, further reducing the volume of blood flowing through the kidneys. This process redirects blood to other organs with more immediate needs. Under severe stress, such as significant blood loss, the sympathetic nervous system kicks into high gear to keep the blood routed to essential organs and keep the body alive. The strong vasoconstriction required to maintain systemic blood pressure under these severe conditions significantly reduces blood flow to the kidneys and can be damaging to the kidney tissues. If blood pressure falls, the sympathetic nerves will also stimulate the release of renin, which we will discuss next.

Renin–Angiotensin–Aldosterone Mechanism

Recall that renin is an enzyme that is produced by the granular cells of the afferent arteriole at the JGA. It enzymatically converts angiotensinogen (made by the liver, freely circulating) into angiotensin I. Its release is stimulated by decreased blood pressure, decreased sodium chloride concentration in the distal convoluted tubule, and sympathetic nervous system stimulation. (Figure 74.1).

Angiotensin-converting enzyme (ACE) enzymatically converts inactive angiotensin I into active angiotensin II. ACE is not a hormone, but it is functionally important in regulating systemic blood pressure and kidney function. It is produced in the lungs but binds to the surfaces of endothelial cells in the afferent arterioles and glomerulus. ACE is important in increasing blood pressure and this is why people with high blood pressure are sometimes prescribed ACE inhibitors to lower their blood pressure.

Angiotensin II is a potent vasoconstrictor that plays an immediate role in the regulation of blood pressure. It acts systemically to cause vasoconstriction as well as constriction of both the afferent and efferent arterioles of the glomerulus. Under the influence of angiotensin II, the efferent arteriole constricts more strongly than the afferent arteriole, increasing GFR. In instances of blood loss or dehydration, angiotensin II reduces both GFR and renal blood flow, thereby limiting fluid loss and preserving blood volume. Its release is usually stimulated by decreases in blood pressure, and so the preservation of adequate blood pressure is its primary role.

This diagram shows the pathway of action of the renin-aldosterone-angiotensin system. An arrow in the center of the image shows the sequence of events that take place, and branching off from this arrow are indications of where in the body these events take place.
Figure 74.1 – Conversion of Angiotensin I to Angiotensin II: The enzyme renin converts the pro-enzyme angiotensin I; the lung-derived enzyme ACE converts angiotensin I into active angiotensin II.
Aldosterone, often called the “salt-retaining hormone,” is released from the adrenal cortex in response to angiotensin II or directly in response to increased plasma K+. It promotes Na+ reabsorption by the nephron, promoting the retention of water. It is also important in regulating K+, promoting its excretion. Aldosterone acts primarily on the distal convoluted tubule (DCT) and the collecting ducts, where it increases the expression of sodium-potassium pumps and sodium channels. This leads to increased reabsorption of sodium and water, and increased excretion of potassium.
Antidiuretic hormone (ADH) promotes the recovery of water, decreases urine volume, and maintains plasma osmolarity and blood pressure. It does so by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts to form water channels, allowing the transcellular movement of water from the lumen of the collecting duct into the interstitial space in the medulla of the kidney by osmosis. From there, it enters the vasa recta capillaries to return to the circulation. Water is attracted by the high osmotic environment of the deep kidney medulla. This process allows for the recovery of large amounts of water from the filtrate back into the blood. In the absence of ADH, these channels are not inserted, resulting in the excretion of water in the form of dilute urine. Therefore, ADH plays a crucial role in concentrating urine and conserving water in the body (Figure 74.2).
This figure shows an aquaporin water channel in the bilayer membrane with water molecules passing through.
Figure 74.2 – Aquaporin Water Channel: Positive charges inside the channel prevent the leakage of electrolytes across the cell membrane, while allowing water to move due to osmosis.

Natriuretic Peptide Hormones

Natriuretic peptide hormones are released in response to increased blood volume and pressure. Atrial natriuretic peptide (ANP) is synthesized and released by the atrial cells of the heart in response to atrial stretch. Brain natriuretic peptide (BNP) is released by ventricular cells. These hormones act on the nephron to increase the excretion of sodium and water. ANP and BNP inhibit the reabsorption of sodium in the distal convoluted tubule and collecting duct, promote vasodilation of the afferent arterioles, and inhibit the release of renin and aldosterone. These actions reduce blood volume and blood pressure.

Adapted from Anatomy & Physiology by Lindsay M. Biga et al, shared under a Creative Commons Attribution-ShareAlike 4.0 International License, chapter 25

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