BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 1 Terms you should understand by the end of this section: diuresis, antidiuresis, osmoreceptors, atrial stretch receptors, renin, juxtaglomerular apparatus (JGA), granular cells, angiotensinogen, angiotensin I, angiotensin II, angiotensin converting enzyme, adrenal cortex, aldosterone, RAAS, intrinsic regulation, macula densa, extrinsic regulation, aldosterone-induced protein (AIP), atrial natriuretic peptide (ANP). I. ADH is the major factor modulating renal control of osmolarity. A. Water is lost in: 1. respiration (controlled by the levels of CO2 and O2 in the body), 2. sweating (controlled based upon body temperature). 3. defecation (controlled by nervous activity in the intestinal tract). 4. urine. B. Regulation takes place in the collecting duct? 1. Most of the filtered fluid is reabsorbed in the proximal tubules. 2. Osmotic and volume regulation must occur by processing only 20-30% of the filtered fluid at most. C. ADH regulates osmolarity directly, although it has an effect on body fluid volume because it regulates the volume of urine produced. 1. Both plasma osmolarity and blood pressure (which varies with blood volume) control the secretion of ADH, but osmolarity appears to be the major variable controlled by ADH. a. ADH modifies the ratio of salt and water lost in the urine (Fig. 18.1). b. With ADH present, more salt than water is lost; with no ADH, much more water than salt is lost. c. The excess ions in the interstitial fluid in diuresis, and the excess water in antidiuresis, are carried away by the vasa recta (Fig. 18.2). notice that, in long-term diruesis (Fig. 18.2 water diuresis ) the maximal gradient in the medulla can decrease to as low as 600 mosm. Diuresis Antidiuresis Fig. 18.1. Diuresis: with no ADH (left), the collecting duct is impermeable to water, so it produces a large amount of dilute urine. Antidiuresis: with maximal ADH (right), the collecting duct is freely permeable to water; produces a small volume of concentrated urine. (Fig. 20-5 in Silverthorn, 5th edition)
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 2 Fig. 18.2. Osmolarity of the renal medulla in antidiuresis (lots of ADH) and diuresis (little ADH). d. ADH causes the epithelial cells lining the collecting duct to insert aquaporins, an evolutionarily ancient water-transporting system, into the membranes lining the tubular lumen (Fig. 18.3). Fig. 18.3. Cellular mechanism of ADH. In response to ADH, epithelial cells in the collecting duct insert aquaporins into the cell membranes facing the tubular fluid, which allows a huge amount of water to enter the cells. The water than diffuses into the interstitial fluid by osmosis. (Fig. 20-6 in Silverthorn, 5th edition) D. Radio-immunoassay has determined that there is an osmotic threshold of 280 mosm/kg for ADH release in humans, so some ADH is released at normal plasma osmolarity (Fig. 18.4). Fig. 18.4. ADH release increases linearly with increased plasma osmolarity above 280 mosm. (Fig. 20-8 in Silverthorn, 5th
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 3 E. Central osmoreceptors (in the hypothalamus) are more sensitive than blood pressure receptors (in the aortic and carotid sinus, as well as atrial stretch receptors) in releasing ADH from the Posterior Pituitary (Fig. 18.5). a. Only when blood pressure becomes very abnormal does it modify the release of ADH. b. A change of only 1% in plasma osmolarity--either up or down--produces enough change in the release of ADH to generate a change in the rate of water loss in the collecting duct. Fig. 18.5. Neural pathways responsible for the release of ADH. Fig. 18.6. Summary of the three major pathways that cause ADH release, and the major target of ADH action in the kidney. (Fig. 20-7 in Silverthorn, 5th F. Several other stimuli modify the release of ADH. 1. ADH release is stimulated by emotion, exercise, anesthesia, and nicotine. 2. ADH release is inhibited by alcohol, caffeine, and CO2 inhalation (which acidifies the plasma).
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 4 II. The renin/angiotensin/aldosterone system (RAAS) controls the fluid volume of the body. Fig. 18.7. The renin-angiotensinaldosterone system (RAAS). Renin activates Angiotensinogen, in the blood stream, where the Angiotensin I becomes Angiotensin II, which releases ADH from the Posterior Pituitary and Aldosterone from the Adrenal Cortex. The total effect is to cause the kidney to retain both Na+ and water. A. Renin is a peptide, secreted by cells of the juxtaglomerular apparatus (JGA) (Fig. 18.8). 1. It is released from granular cells of the JGA in response to decreased blood pressure (volume). 2. Immediate stimuli for release: a. a decrease in the Cl- concentration of the fluid in the thick ascending limb of the loop of Henle. b. a decrease in perfusion pressure in the afferent arteriole. 3. The [Cl-] sensing cells are in the macula densa of the thick ascending limb of the loop of Henle. 4. Renin is released into the afferent arterioles. Fig. 18.8. Anatomy of a nephron and its associate capillary system (the vasa recta), showing the location of the macula densa (in the thick ascending limb of the loop of Henle) and the juxtaglomerular apparatus (JGA) in the afferent arteriole.
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 5 B. Renin is an enzyme; its substrate is angiotensinogen. 1. Angiotensinogen is a 14-amino acid peptide found in the a2 globulin fraction of plasma. 2. Renin removes a tetrapeptide from one end to yield a decapeptide, angiotensin I. (Angiotensin I has no known physiological activity.) 4. Angiotensin converting enzyme, found in the lungs and in the kidney, then removes two more amino acids to produce angiotensin II, which has several effects: a. It produces a strong vasoconstriction by smooth muscles in vessel walls to contract. b. It stimulates brain neurons that: i. produce sympathetic nervous signals to contract smooth muscles in blood vessels. ii. stimulate drinking and salt hunger. iii. triggers the release of ADH and ACTH. iv. cause cells of the adrenal cortex to produce and release aldosterone. C. Aldosterone modifies the reabsorption of Na + in the collecting duct (and water passively follows the reabsorption of Na + ), so that isotonic NaCl solution is reabsorbed (Fig. 18.9). 1. Aldosterone acts through aldosterone-induced proteins (AIPs) to: a. activate the Na + -K + ATPase. (It has been shown that it is not the ATPase itself.) b. increase permeability of Na + through the luminal membrane of the cells, making Na + more available to the ATPase. c. increase energy-producing metabolic processes to provide energy for the pump. Fig. 18.9. Mechanism of action of aldosterone on cells in the distal tubule. (Fig. 20-12 in Silverthorn, 5 th 2. This action modifies both Na + and K + concentration in body fluids. 3. Na + is the primary extracellular cation in the body, so changing how much Na + is reabsorbed can significantly affect the volume of urine excreted. 4. In fact, the Na + uptake that can be controlled by aldosterone probably only accounts for 2% or less of the total Na + filtered into the nephron, but over time that is a lot.
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 6 5. CONCLUSION: because it causes the isotonic reabsorption of solute and water, aldosterone cannot affect the osmolarity of body fluids; instead, it primarily controls is body fluid volume. D. The renin-angiotensin system regulates kidney function by two major mechanisms: 1. Intrinsic control: maintains homeostasis of the GFR. a. GFR remains constant even if renal blood pressure varies from 80 to 180 mmhg. b. This regulation may occur in each individual nephron (single nephron GFR= SNGFR). c. Renin is released by the granular cells of the macula densa into the afferent arteioles, in response to lowered [Cl - ] in tubular fluid, which occurs when the filtration rate decreases. d. The renin => angiotensinogen => angiotensin I => angiotensin II takes place fast enough to increase smooth muscle contraction in the walls of the efferent arterioles. Fig. 18.10. Intrinsic control of GFR by the RAAS acting on the efferent arteriole. (Fig. 19-10 in Silverthorn, 5 th 2. Extrinsic control: the RAAS. a. As in intrinsic control, renin acts on circulating angiotensinogen. i. Extrinsic control requires much more renin to be released, so the threshold for this hormonal control loop is higher than the threshold for intrinsic control. ii. Control of the synthesis and release of angiotensinogen is not well understood. E. The net effect of the RAAS is to prevent (1) Na + depletion and (2) decreased blood pressure. 1. Loss of body Na + or a reduction in arterial blood pressure produces a reduction in renal perfusion pressure, which then stimulates renin release. a. Renin release is controlled by many factors. Among them are: i. Activity of receptors located in the juxtaglomerular apparatus where it touches the walls of the afferent arteriole. (Effective stimulus for release is a drop in perfusion pressure.) ii. Receptors in the macula densa. (Effective stimulus is a decrease in the Cl - concentration of tubular fluid in the ascending thick limb.) iii. ß-adrenergic receptors on the granular cells. (Effective stimulus is circulating catecholamines.) b. Once renin is released it remains in the circulation for tens of minutes.
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 7 Fig. 18.11. Functional summary of the RAAS. (Fig. 20-13 in Silverthorn, 5th 2. Renin triggers two mechanisms to increase abnormally low blood pressure: a. Angiotensin raises blood pressure directly by increasing the peripheral resistance. b. Aldosterone saves salt and maintains blood pressure by maintaining body fluid volume. 3. Abnormally high release of renin can produce pathological hypertension by these same mechanisms. It is thought to be one of the causes of "essential hypertension". 4. The renin-angiotensin system does have an effect on body osmolarity: it potentiates ADH release in response to osmotic stimuli. Fig. 18.12. Summary of the mechanisms that trigger renin secretion in the body. (Fig. 20-14 in Silverthorn, 5th
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 8 Fig. 18.13. Interactions between intrinsic and extrinsic mechanisms used to regulate GFR which regulates plasma volume and blood pressure. III. Atrial natriuretic peptide (ANP), also contributes to the regulation of body fluid volume. ("Natri" is a prefix that refers to sodium. The name refers to the effect of the hormone--increasing the excretion of Na + into the urine.) A. ANP is released in response to distention of the atria, which occurs--for example--when venous return increases greatly following volume loading. 1. ANP is a 28-amino acid peptide. 2. It is released from cells in the walls of the atria in response to activation of atrial stretch receptors. 3. It acts upon the collecting duct to increase Na + excretion and upon the afferent and efferent arterioles to increase glomerular filtration rate. 4. Its mechanism is still being studied, but ANF may act by changing Na + -selective channels in the tubular membrane into Ca ++ -selective channels, excluding Na +.
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 9 Fig. 18.14. Summary of the various effects of ANP. (Fig. 20-15 in Silverthorn, 5 th SUMMARY OF THE MAJOR HORMONES THAT AFFECT PLASMA VOLUME Hormone Stimulus Source Effects ADH Increased plasma osmolarity; decreased blood pressure or blood volume Hypothalamus-- neurohypophysis Renin Aldosterone Atrial natriuretic factor Decreased blood pressure or blood volume Increased circulating angiotensin II; increased plasma [K + ] Increased plasma volume Granule cells of juxtaglomerular apparatus (JGA) Adrenal cortex Cells in the atria Increase water permeability of epithelial cells along the collecting duct; increase urea permeability of same cells Increase circulating angiotensin I Increase activity of Na + /K + ATPase in cells along collecting duct Decrease permeability of epithelial cells along the collecting duct to Na +
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 10 IV. Integrated responses to variations in volume and osmolarity of body fluids. A. There are 8 combinations of abnormal conditions in volume and osmolarity. Fig. 18.15. The 8 possible disturbances in body fluid osmolarity and volume, with an example of how they are caused. (Fig. 20-16 in Silverthorn, 5th B. We will consider 2 of the possible disturbances (you should be able to discuss all 8). 1. Eating salt increases the body s osmolarity without changing its fluid volume. Fig. 18.16. Eating NaCl causes a quick increase in drinking and ADH release, which compensates for the increase in osmolarity, but it causes an increase in volume. The increased volume causes a slower decrease in the retention of NaCl, by shutting off the release of aldosterone, so that the excess NaCl is slowly removed from the body. (Fig. 20-16 in Silverthorn, 5th
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 11 2. Sweating or diarrhea decreases the volume of body fluid and increases its osmolarity. Fig. 18.17. Severe dehydration causes a complex responses, as discussed in the text of the outline. (Fig. 20-17 in Silverthorn, 5 th a. Decreasing the blood volume would decrease the blood pressure. i. This would activate cardiovascular mechanisms to increase blood pressure. ii. This would also activate the RAAS, which would retain NaCl; this is good for building up the volume, but this would also increase osmolarity, which is already too high. There is an interesting solution to this problem (see below). iii. If the volume loss is great enough, the GFR decreases, which helps to conserve volume. iv. The baroreceptors and atrial volume receptors would cause some release of ADH, which conserves volume and lowers the osmolarity. b. Increasing the osmolarity greatly increases thirst (and water intake) and releases lots of ADH. i. This helps to restore both osmolarity and volume. ii. But what about the aldosterone problem? The lowered volume will cause it to retain NaCl and oppose the action of ADH. There are two solutions: The thirst and ADH systems are fast and aldosterone is slow; the problem may be resolved before aldosterone exerts its effects.
BIPN100 F15 Human Physiology (Kristan) Lecture 18: Endocrine control of renal function. p. 12 A large increase in osmolarity inhibits the release of aldosterone. In this way, the RAAS can have its effects on the cardiovascular system (increasing the blood pressure) without interfering with the effects of fluid intake and ADH. V. The grand summary. A. Renin, angiotensin, aldosterone, and ANP are primarily involved in volume control (left portion of Fig. 18.18). B. ADH and osmoreceptors are primarily involved in osmolarity control (right portion of Fig. 18.18). C. There are two major interactions between the two controlling mechanisms: 1. ADH causes vasoconstriction (dashed line). 2. The action of aldosterone affects plasma osmolarity as well as plasma volume. D. Both systems affect blood pressure and blood volume; these effects are diagramed in Fig. 14.10 from the notes to lecture 14. Fig. 18.18. The major regulatory systems regulating the volume of body water and its osmolarity.