Objectives
Upon completion of this chapter, the student should be able to answer the following questions:
- •
Why do changes in water balance result in alterations in the [Na + ] of the extracellular fluid?
- •
How is the secretion of arginine vasopressin controlled by changes in the osmolality of the body fluids and in blood volume and pressure?
- •
What are the cellular events associated with the action of arginine vasopressin on the collecting duct, and how do they lead to an increase in the water permeability of this segment?
- •
What is the role of Henle’s loop in the production of both dilute and concentrated urine?
- •
What is the composition of the medullary interstitial fluid, and how does it participate in the process of producing concentrated urine?
- •
What are the roles of the vasa recta in the process of diluting and concentrating the urine?
- •
How is the diluting and concentrating ability of the kidneys quantitated?
Key Terms
Insensible water loss
Positive water balance
Negative water balance
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH)
Diuresis
Antidiuresis
Supraoptic nuclei
Paraventricular nuclei
Neurohypophysis (posterior pituitary)
Osmoreceptors
Effective osmole
Ineffective osmole
Set point (for osmotic control of AVP secretion)
Baroreceptors
Polyuria
Polydipsia
Central diabetes insipidus
Pituitary diabetes insipidus
Syndrome of inappropriate AVP (ADH) secrection (SIADH)
Syndrome of inappropriate antidiuresis (SIAD)
Aquaporin (AQP)
V 2 receptor
Nephrogenic syndrome of inappropriate antidiuresis
Nephrogenic diabetes insipidus
Thirst
8 × 8 recommendation
Concurrent multiplication (by Henle’s loop)
Single effect
Water diuresis
Diluting segment (thick ascending limb of Henle’s loop)
Vasa recta
Solute-free water
Free-water clearance ( <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='CH2O’>CH2OCH2O
C H 2 O
)
Osmolar clearance (C osm )
Tubular conservation of water <SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='TH2OC’>TCH2OTH2OC
T H 2 O C
As described in Chapter 1 , water constitutes approximately 60% of the healthy adult human body. Body water is divided into two compartments (i.e., intracellular fluid [ICF] and extracellular fluid [ECF]), which are in osmotic equilibrium. Water intake into the body generally occurs orally, and the water ingested is absorbed into the ECF by the gastrointestinal tract. However, in clinical situations, intravenous infusion is an important route of water entry. Regardless of the route of entry (oral versus intravenous), water first enters the ECF and then equilibrates with the ICF. The kidneys are responsible for regulating water balance and under most conditions are the major route for elimination of water from the body ( Table 5.1 ). Other routes of water loss from the body include evaporation from the cells of the skin and respiratory passages. Collectively, water loss by these routes is termed insensible water loss , because people are unaware of its occurrence. The production of sweat accounts for the loss of additional water. Water loss by this mechanism can increase dramatically in a hot environment, with exercise, or in the presence of fever ( Table 5.2 ). Finally, water can be lost from the gastrointestinal tract. Fecal water loss is normally small (∼100 mL/day) but can increase dramatically with diarrhea (e.g., 20 L/day in persons with cholera). Vomiting also can cause gastrointestinal water loss.
| Route | mL/day |
|---|---|
| Water Intake | |
| Fluid ∗ | 1200 |
| In food | 1000 |
| Metabolically produced from food | 300 |
| Total | 2500 |
| Water Output | |
| Insensible | 700 |
| Sweat | 100 |
| Feces | 200 |
| Urine | 1500 |
| Total | 2500 |
∗ Fluid intake varies widely for both social and cultural reasons.
| Source of Water Loss | Normal Temperature (mL/day) | Hot Weather ∗ (mL/day) | Prolonged Heavy Exercise ∗ (mL/day) |
|---|---|---|---|
| Insensible Loss | |||
| Skin | 350 | 350 | 350 |
| Lungs | 350 | 250 | 650 |
| Sweat | 100 | 1400 | 5000 |
| Feces | 200 | 200 | 200 |
| Urine ∗ | 1500 | 1200 | 500 |
| Total loss | 2500 | 3400 | 6700 |
∗ In hot weather and during prolonged heavy exercise, water balance is maintained by increased water ingestion. Decreased excretion of water by the kidneys alone is insufficient to maintain water balance.
Although water loss from sweating, defecation, and evaporation from the lungs and skin can vary depending on the environmental conditions or during pathologic conditions, the loss of water by these routes cannot be regulated. In contrast, the renal excretion of water is tightly regulated to maintain whole-body water balance. The maintenance of water balance requires that water intake and loss from the body are precisely matched. If intake exceeds losses, positive water balance exists. Conversely, when intake is less than losses, negative water balance exists.
When water intake is low or water losses increase, the kidneys conserve water by producing a small volume of urine that is hyperosmotic with respect to plasma. When water intake is high, a large volume of hypoosmotic urine is produced. In a healthy person the urine osmolality (U osm ) can vary from approximately 50 to 1200 mOsm/kg H 2 O, and the corresponding urine volume can vary from approximately 18 to 0.5 L/day.
It is important to recognize that disorders of water balance are manifested by alterations in the body fluid osmolality, which can be assessed by measuring plasma osmolality (P osm ). Because the major determinant of plasma osmolality is Na + (with its anions Cl − and HCO 3 – ), these disorders also result in alterations in the plasma [Na + ] ( Fig. 5.1 ). When an abnormal plasma [Na + ] is observed in an individual, it is tempting to suspect a problem in Na + balance. However, the problem usually is related to water balance, not Na + balance. As described in Chapter 6 , changes in Na + balance usually result in alterations in the volume of the ECF, not its osmolality.
When plasma osmolality (P osm ) is reduced (i.e., hypoosmolality), water moves from the ECF into cells, causing them to swell. Symptoms associated with hypoosmolality are related primarily to swelling of brain cells. For example, a rapid decrease in P osm can alter neurologic function and thereby cause nausea, malaise, headache, confusion, lethargy, seizures, and coma. When P osm is increased (i.e., hyperosmolality), water is lost from cells, causing them to shrink. The symptoms of an increase in P osm also are primarily neurologic and include lethargy, weakness, seizures, coma, and even death.
The symptoms associated with changes in body fluid osmolality vary depending on how quickly osmolality is changed. Rapid changes in osmolality (i.e., over hours) are less well tolerated than changes that occur more gradually (i.e., over days to weeks). Indeed, when alterations in body fluid osmolality have developed over an extended period, such persons may be entirely asymptomatic. This situation reflects the ability of cells over time either to eliminate intracellular osmoles, as occurs with hypoosmolality, or to generate new intracellular osmoles in response to hyperosmolality and thus minimize changes in cell volume of the neurons.
Under steady-state conditions, the kidneys control water excretion more or less independently of their ability to control the excretion of various other physiologically important substances ( Fig. 5.2 ). This ability allows water balance to be achieved without upsetting the other homeostatic functions of the kidneys.
This chapter discusses the mechanisms by which the kidneys maintain water balance by excreting either hypoosmotic (dilute) or hyperosmotic (concentrated) urine (see Fig. 5.2 ). The control of arginine vasopressin (AVP) secretion and its important role in regulating the excretion of water by the kidneys also are explained.
Arginine Vasopressin
AVP, also known as antidiuretic hormone (ADH) , acts on the kidneys to regulate the volume and osmolality of the urine. When plasma AVP levels are low, a large volume of urine is excreted ( diuresis ) and the urine is dilute. a
a Diuresis is simply a large urine output. When the urine contains primarily water, it is referred to as a water diuresis, which is in contrast to the diuresis seen with the administration of diuretic agents (see Chapter 10 ). In the latter case, urine output is large, but the urine contains solute plus water, which sometimes is termed a solute diuresis
When plasma AVP levels are high, a small volume of urine is excreted ( antidiuresis ) and the urine is concentrated. Fig. 5.2 illustrates the effect of AVP on the urine flow rate and osmolality.AVP is a small peptide that is nine amino acids long. It is synthesized in neuroendocrine cells located within the supraoptic and paraventricular nuclei of the hypothalamus. b
b Neurons within the supraoptic and paraventricular nuclei synthesize either AVP or the related peptide oxytocin. AVP-secreting neurons predominate in the supraoptic nucleus, and the oxytocin-secreting neurons are found primarily in the paraventricular nucleus
The synthesized hormone is packaged in granules that are transported down the axon of the neuron and stored in the nerve terminals located in the neurohypophysis (posterior pituitary). The anatomy of the hypothalamus and pituitary gland is shown in Fig. 5.3 .
The secretion of AVP by the posterior pituitary can be influenced by several factors. The two primary physiologic regulators of AVP secretion are the osmolality of the body fluids (osmotic) and volume and pressure of the vascular system (hemodynamic). Other factors that can alter AVP secretion include nausea (stimulates), atrial natriuretic peptide (inhibits), and angiotensin II (stimulates). Several drugs, prescription and nonprescription, also affect AVP secretion. For example, nicotine stimulates secretion, whereas ethanol inhibits secretion.
The gene for arginine vasopressin (AVP) is found on chromosome 20. It contains approximately 2000 base pairs with three exons and two introns. The gene codes for a 145-amino-acid prohormone that consists of a signal peptide, the AVP molecule, neurophysin, and a glycopeptide (copeptin). As the cell processes the prohormone, the signal peptide is cleaved off in the rough endoplasmic reticulum. Once packaged in neurosecretory granules, the preprohormone is further cleaved into AVP, neurophysin, and copeptin molecules. The neurosecretory granules are then transported down the axon to the posterior pituitary and stored in the nerve endings until released. When the neurons are stimulated to secrete AVP, the action potential opens Ca ++ channels in the nerve terminal, which raises the intracellular [Ca ++ ] and causes exocytosis of the neurosecretory granules. All three peptides are secreted in this process. Neurophysin and copeptin do not have an identified physiologic function.
Osmotic Control of Arginine Vasopressin Secretion
Changes in the osmolality of body fluids play the most important role in regulating AVP secretion; changes as minor as 1% are sufficient to alter it significantly. Although the neurons in the supraoptic and paraventricular nuclei respond to changes in body fluid osmolality by altering their secretion of AVP, cells in the anterior hypothalamus also sense changes in body fluid osmolality and regulate the activity of the AVP-secreting neurons. These cells, termed osmoreceptors , sense changes in body fluid osmolality by either shrinking or swelling. c
c Osmoreceptors have been identified in the anterior hypothalamus; one of these sites is the organum vasculosum of the lamina terminalis, which is located outside the blood-brain barrier. In addition, the subfornical organ, which is also located in the anterior hypothalamus outside the blood-brain barrier, responds to circulating levels of angiotensin II, which stimulates AVP secretion.
The osmoreceptors respond only to solutes in plasma that are effective osmoles (see Chapter 1 ). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus elevation of the plasma urea concentration alone has little or no effect on AVP secretion.When the effective osmolality of the plasma increases, the osmoreceptors send signals to the AVP-synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and AVP synthesis and secretion are stimulated. Conversely, when the effective osmolality of the plasma is reduced, secretion is inhibited. Because AVP is rapidly degraded in the plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited. As a result, the AVP system can respond rapidly to fluctuations in body fluid osmolality.
Fig. 5.4A illustrates the effect of changes in plasma osmolality on circulating AVP levels. The set point of the system is the plasma osmolality value at which AVP secretion begins to increase. Below this set point, virtually no AVP is released. Above this set point, the slope of the relationship is quite steep and accounts for the sensitivity of this system. The set point varies among individuals and is genetically determined. In healthy adults it varies from 275 to 290 mOsm/kg H 2 O (average ∼280 to 285 mOsm/kg H 2 O). As described later in this chapter, the set point shifts in response to changes in blood volume and pressure. It also shifts during pregnancy, with the osmolality of the mother’s body fluids decreasing during the third trimester. The reasons for the shift of the set point during pregnancy are not completely known but likely involve hormones (e.g., relaxin and chorionic gonadotropin) whose circulating levels are elevated during pregnancy.
Hemodynamic Control of Arginine Vasopressin Secretion
A decrease in blood volume or pressure also stimulates AVP secretion. The receptors responsible for this response are in both the low-pressure (left atrium and large pulmonary vessels) and the high-pressure (aortic arch and carotid sinus) sides of the circulatory system. Because the low-pressure receptors are in the high-compliance side of the circulatory system (i.e., venous) and most blood is in the venous side of the circulatory system, these low-pressure receptors respond to vascular volume. The high-pressure receptors respond to arterial pressure. Both groups of receptors are sensitive to stretch of the wall of the structure in which they are located and are termed baroreceptors . Signals from these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure. Signals then are relayed from the brainstem to the AVP secretory cells of the supraoptic and paraventricular hypothalamic nuclei. The sensitivity of the baroreceptor system is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before AVP secretion is stimulated. This phenomenon is illustrated in Fig. 5.4B . Many substances have been found to alter the secretion of AVP through their effects on blood pressure. These substances include bradykinin and histamine, which lower pressure and thus stimulate AVP secretion, and norepinephrine, which increases blood pressure and inhibits AVP secretion.
Alterations in blood volume and pressure also affect the response to changes in body fluid osmolality ( Fig. 5.5 ). With a decrease in blood volume or pressure, the set point is shifted to lower osmolality values and the slope of the relationship is steeper. In terms of survival of the individual this means that when faced with circulatory collapse, the kidneys continue to conserve water, even though by doing so they reduce the osmolality of the body fluids. With an increase in blood volume or pressure, the opposite occurs. The set point is shifted to higher osmolality values, and the slope is decreased.
Arginine Vasopressin Actions on the Kidneys
The primary action of AVP on the kidneys is to increase the permeability of the collecting duct to water and thereby decrease urine volume (see Fig. 5.2 ). In addition, AVP increases the permeability of the medullary portion of the collecting duct to urea and stimulates sodium chloride (NaCl) reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. Because of these later two actions of AVP, it can cause small and variable changes in the excretion of NaCl and urea.
AVP’s primary action on the kidney is to regulate water reabsorption by the collecting duct. However, as noted, AVP also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. This effect of AVP is mediated by activation of the V 2 receptor and is thought to be important in maintaining the hyperosmotic medullary interstitium at a time when AVP is also increasing collecting duct water reabsorption (see later in the chapter). AVP also acts on vascular smooth muscle, via a different receptor (V 1 receptor), causing vasoconstriction and elevating blood pressure. This vascular effect can increase renal Na + excretion by elevating pressure in the peritubular capillaries and thereby inhibiting proximal tubule Na + reabsorption (see Chapter 4 ). As a result of these competing effects, AVP may either increase or decrease NaCl excretion. What determines which response predominates is the plasma level of AVP. With low to moderate AVP levels, the V 2 -mediated response predominates and NaCl excretion is decreased. With high AVP levels, the V 1 -mediated response predominates and NaCl excretion is increased. It is important to note that even when NaCl excretion is increased in the setting of high AVP levels, NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct is still stimulated. However, the resorptive capacity of these segments is overwhelmed by the NaCl delivered to these segments from the proximal tubule, and as result, NaCl excretion is increased.
Inadequate release of AVP from the posterior pituitary results in excretion of large volumes of dilute urine ( polyuria ). To compensate for this loss of water, the individual must ingest large volumes of water ( polydipsia ) to maintain constant body fluid osmolality. If the individual is deprived of water, the body fluids become hyperosmotic. This condition is called central diabetes insipidus or pituitary diabetes insipidus. Central diabetes insipidus can be inherited, although this situation is rare. It occurs more commonly after head trauma and with brain neoplasms or infections. Persons with central diabetes insipidus have a urine-concentrating defect that can be corrected by the administration of exogenous AVP.
The inherited (autosomal dominant) form of central diabetes insipidus is caused by a variety of mutations in the AVP gene. In patients with this form of central diabetes insipidus, mutations have been identified in all regions of the AVP gene (i.e., AVP, copeptin, and neurophysin). The most common mutation is found in the neurophysin portion of the gene. In each of these situations, defective trafficking of the peptide occurs, with abnormal accumulation in the endoplasmic reticulum. It is believed that this abnormal accumulation in the endoplasmic reticulum results in death of the AVP secretory cells of the supraoptic and paraventricular nuclei.
The syndrome of inappropriate AVP (ADH) secretion (SIADH) is a common clinical problem characterized by plasma AVP levels that are elevated above what would be expected based on body fluid osmolality and blood volume and pressure—hence the term inappropriate AVP (ADH) secretion. When AVP levels are chronically elevated, the collecting duct overexpresses water channels, thus augmenting the effect of AVP on the kidney. Because not all patients who have inappropriate antidiuresis have elevated AVP levels, the term syndrome of inappropriate antidiuresis (SIAD) is used. Persons with SIADH/SIAD retain water, and their body fluids become progressively hypoosmotic. In addition, their urine is more hyperosmotic than expected based on the low body fluid osmolality. SIADH/SIAD can be caused by infections and neoplasms of the brain, drugs (e.g., antitumor drugs), pulmonary diseases, and carcinoma of the lung. Many of these conditions stimulate AVP secretion by altering neural input to the AVP secretory cells. However, small cell carcinoma of the lung produces and secretes many peptides, including AVP.
Recently, nonpeptide vasopressin receptor antagonists (e.g., conivaptan and tolvaptan) have been developed that can be used to treat SIADH/SIAD and other conditions in which AVP-dependent water retention by the kidneys occurs (e.g., congestive heart failure and hepatic cirrhosis).
In the absence of AVP, the apical membrane of principal cells (see Chapter 2 ), located in the later portion of the distal tubule and along the collecting duct, is relatively impermeable to water. This reflects the fact that in the absence of AVP the apical membrane of these cells contains few water channels ( aquaporins [AQPs] ). Thus, in the absence of AVP, little water is reabsorbed by these nephron segments. Binding of AVP to its cognate receptor (V 2 ) located in the basolateral membrane of principal cells results in the insertion of aquaporin-2 (AQP2) water channels into the apical membrane, allowing water to enter the cell from the tubule lumen. This water then exits the cell across the basolateral membrane, which is always freely permeable to water as a result of the presence of aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels. Thus, in the presence of AVP, water is reabsorbed from the tubule lumen.
AVP also regulates the abundance of AQP2 (and AQP3). When large volumes of water are ingested over an extended period (e.g., psychogenic polydipsia), the abundance of AQP2 and AQP3 in principal cells is reduced. Therefore when water ingestion is restricted, these individuals cannot immediately maximally concentrate their urine. Conversely, in states of restricted water ingestion, AQP2 and AQP3 protein abundance in principal cells increases, thereby facilitating the excretion of maximally concentrated urine.
It is also clear that abundance of AQP2 (and in some instances also AQP3) varies in pathologic conditions associated with disturbances in urine concentration and dilution. AQP2 abundance is reduced in several conditions associated with impaired urine concentrating ability, such as hypercalcemia or hypokalemia. By contrast, in conditions associated with water retention, such as congestive heart failure, hepatic cirrhosis, and pregnancy, AQP2 abundance is increased.
AVP also increases the permeability of the terminal portion of the inner medullary collecting duct to urea. This increase in permeability results in an increase in urea reabsorption and an increase in the osmolality of the medullary interstitial fluid. The inner medullary collecting duct expresses two different urea transporters, UT-A1 and UT-A3. UT-A1 is localized primarily to the apical membrane and UT-A3 is localized primarily to the basolateral membrane. AVP, acting through adenylyl cyclase and the cyclic adenosine monophosphate (cAMP)/protein kinase A cascade, increases the abundance of both UT-1 and UT-3, thus increasing the permeability of this portion of the collecting duct to urea. Increasing the osmolality of the interstitial fluid of the renal medulla also increases the permeability of the collecting duct to urea. This effect is mediated by the phospholipase C/protein kinase C pathway, which also increases UT-1 and UT-3 abundance. This effect is separate from and additive to that of AVP.
AVP also stimulates the reabsorption of NaCl by the thick ascending limb of Henle’s loop and by the distal tubule and collecting duct. This increase in Na + reabsorption is due to an increased abundance of three Na + transporters: 1Na + -1K + -2Cl – symporter (thick ascending limb of Henle’s loop), Na + -Cl – symporter (distal tubule), and Na + channel (epithelial sodium channel [ENaC], in the later portion of the distal tubule and collecting duct). Stimulation of thick ascending limb and collecting duct NaCl transport helps maintain the hyperosmotic medullary interstitium that is necessary for the absorption of water from the medullary portion of the collecting duct (see later).
The gene for the V2 receptor is located on the X chromosome. It codes for a 371-amino-acid protein that is in the family of receptors that have seven membrane-spanning domains and are coupled to heterotrimeric G proteins. As shown in Fig. 5.6 , binding of AVP to its receptor on the basolateral membrane activates adenylyl cyclase. The increase in intracellular cAMP then activates protein kinase A, which results in phosphorylation of AQP2 water channels, which reduces the endocytic removal of AQP2 from the apical membrane and results in increased transcription of the AQP2 gene through activation of a cAMP response element. AVP also increases the rate of insertion of vesicles containing AQP2 into the apical membrane by facilitating their movement along microtubules driven by the molecular motor dynein. Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP2 and facilitate the fusion of these vesicles with the membrane. The net addition of AQP2 to the apical membrane, resulting from reduced endocytosis and increased insertion, allows more water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality). The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels, which are constitutively present in the basolateral membrane. When the V 2 receptor is not occupied by AVP, clathrin-mediated endocytosis of AQP2 is enhanced and the exocytic insertion of AQP2 into the membrane is reduced, which decreases the total number of AQP2 channels in the apical membrane, rendering the apical membrane once again impermeable to water. The endocytosed AQP2 molecules may be either stored in cytoplasmic vesicles, ready for reinsertion into the apical membrane when AVP levels in the plasma increase, or degraded.
Recently individuals have been identified who have activating (gain-of-function) mutations in the V 2 receptor gene. Thus the receptor is constitutively activated even in the absence of AVP. These individuals have laboratory findings like those seen in SIAD, including reduced plasma osmolality, hyponatremia (reduced plasma [Na + ]), and urine more concentrated than would be expected from the reduced body fluid osmolality. In these individuals, plasma levels of AVP are low, and not elevated as seen in more common causes of SIAD where plasma AVP are elevated and thus responsible for the antidiuresis. This form of SIAD has been termed nephrogenic syndrome of inappropriate antidiuresis.
The collecting ducts of some individuals do not respond normally to AVP. These individuals cannot maximally concentrate their urine and consequently have polyuria and polydipsia. This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from several systemic disorders and, more rarely, occurs because of inherited disorders. Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of AQP2 in the collecting duct. Decreased expression of AQP2 has been documented in the urine-concentrating defects associated with hypokalemia, lithium ingestion (some degree of nephrogenic diabetes insipidus develops in 35% of persons who take lithium for bipolar disorder), ureteral obstruction, a low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the AVP receptor (V 2 receptor) gene or the AQP2 gene. Approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V 2 receptor gene, with the other 10% being the result of mutations in the AQP2 gene. Because the gene for the V 2 receptor is located on the X chromosome, these inherited forms are X linked. Most of these mutations result in trapping of the receptor in the endoplasmic reticulum of the cell; only a few cases result in the surface expression of a V 2 receptor that does not bind AVP. The gene coding for AQP2 is located on chromosome 12 and is inherited as both an autosomal recessive and an autosomal dominant defect. As noted in Chapter 1, Chapter 4 , AQPs exist as homotetramers. This homotetramer formation explains the difference between the two forms of nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP2 and defective AQP2 molecules. The defective AQP2 monomer is not delivered to the plasma membrane, and thus the homotetramers that do form contain only normal AQP2 molecules. Accordingly, mutations in both alleles would be required to produce nephrogenic diabetes insipidus. In the autosomal dominant form, the defective monomers can form tetramers with normal monomers, as well as defective monomers. However, these tetramers cannot be delivered to the plasma membrane.
The gene for arginine vasopressin (AVP) is found on chromosome 20. It contains approximately 2000 base pairs with three exons and two introns. The gene codes for a 145-amino-acid prohormone that consists of a signal peptide, the AVP molecule, neurophysin, and a glycopeptide (copeptin). As the cell processes the prohormone, the signal peptide is cleaved off in the rough endoplasmic reticulum. Once packaged in neurosecretory granules, the preprohormone is further cleaved into AVP, neurophysin, and copeptin molecules. The neurosecretory granules are then transported down the axon to the posterior pituitary and stored in the nerve endings until released. When the neurons are stimulated to secrete AVP, the action potential opens Ca ++ channels in the nerve terminal, which raises the intracellular [Ca ++ ] and causes exocytosis of the neurosecretory granules. All three peptides are secreted in this process. Neurophysin and copeptin do not have an identified physiologic function.
Osmotic Control of Arginine Vasopressin Secretion
Changes in the osmolality of body fluids play the most important role in regulating AVP secretion; changes as minor as 1% are sufficient to alter it significantly. Although the neurons in the supraoptic and paraventricular nuclei respond to changes in body fluid osmolality by altering their secretion of AVP, cells in the anterior hypothalamus also sense changes in body fluid osmolality and regulate the activity of the AVP-secreting neurons. These cells, termed osmoreceptors , sense changes in body fluid osmolality by either shrinking or swelling. c
c Osmoreceptors have been identified in the anterior hypothalamus; one of these sites is the organum vasculosum of the lamina terminalis, which is located outside the blood-brain barrier. In addition, the subfornical organ, which is also located in the anterior hypothalamus outside the blood-brain barrier, responds to circulating levels of angiotensin II, which stimulates AVP secretion.
The osmoreceptors respond only to solutes in plasma that are effective osmoles (see Chapter 1 ). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus elevation of the plasma urea concentration alone has little or no effect on AVP secretion.When the effective osmolality of the plasma increases, the osmoreceptors send signals to the AVP-synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and AVP synthesis and secretion are stimulated. Conversely, when the effective osmolality of the plasma is reduced, secretion is inhibited. Because AVP is rapidly degraded in the plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited. As a result, the AVP system can respond rapidly to fluctuations in body fluid osmolality.
Fig. 5.4A illustrates the effect of changes in plasma osmolality on circulating AVP levels. The set point of the system is the plasma osmolality value at which AVP secretion begins to increase. Below this set point, virtually no AVP is released. Above this set point, the slope of the relationship is quite steep and accounts for the sensitivity of this system. The set point varies among individuals and is genetically determined. In healthy adults it varies from 275 to 290 mOsm/kg H 2 O (average ∼280 to 285 mOsm/kg H 2 O). As described later in this chapter, the set point shifts in response to changes in blood volume and pressure. It also shifts during pregnancy, with the osmolality of the mother’s body fluids decreasing during the third trimester. The reasons for the shift of the set point during pregnancy are not completely known but likely involve hormones (e.g., relaxin and chorionic gonadotropin) whose circulating levels are elevated during pregnancy.
Hemodynamic Control of Arginine Vasopressin Secretion
A decrease in blood volume or pressure also stimulates AVP secretion. The receptors responsible for this response are in both the low-pressure (left atrium and large pulmonary vessels) and the high-pressure (aortic arch and carotid sinus) sides of the circulatory system. Because the low-pressure receptors are in the high-compliance side of the circulatory system (i.e., venous) and most blood is in the venous side of the circulatory system, these low-pressure receptors respond to vascular volume. The high-pressure receptors respond to arterial pressure. Both groups of receptors are sensitive to stretch of the wall of the structure in which they are located and are termed baroreceptors . Signals from these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure. Signals then are relayed from the brainstem to the AVP secretory cells of the supraoptic and paraventricular hypothalamic nuclei. The sensitivity of the baroreceptor system is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before AVP secretion is stimulated. This phenomenon is illustrated in Fig. 5.4B . Many substances have been found to alter the secretion of AVP through their effects on blood pressure. These substances include bradykinin and histamine, which lower pressure and thus stimulate AVP secretion, and norepinephrine, which increases blood pressure and inhibits AVP secretion.
Alterations in blood volume and pressure also affect the response to changes in body fluid osmolality ( Fig. 5.5 ). With a decrease in blood volume or pressure, the set point is shifted to lower osmolality values and the slope of the relationship is steeper. In terms of survival of the individual this means that when faced with circulatory collapse, the kidneys continue to conserve water, even though by doing so they reduce the osmolality of the body fluids. With an increase in blood volume or pressure, the opposite occurs. The set point is shifted to higher osmolality values, and the slope is decreased.
Arginine Vasopressin Actions on the Kidneys
The primary action of AVP on the kidneys is to increase the permeability of the collecting duct to water and thereby decrease urine volume (see Fig. 5.2 ). In addition, AVP increases the permeability of the medullary portion of the collecting duct to urea and stimulates sodium chloride (NaCl) reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. Because of these later two actions of AVP, it can cause small and variable changes in the excretion of NaCl and urea.
AVP’s primary action on the kidney is to regulate water reabsorption by the collecting duct. However, as noted, AVP also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. This effect of AVP is mediated by activation of the V 2 receptor and is thought to be important in maintaining the hyperosmotic medullary interstitium at a time when AVP is also increasing collecting duct water reabsorption (see later in the chapter). AVP also acts on vascular smooth muscle, via a different receptor (V 1 receptor), causing vasoconstriction and elevating blood pressure. This vascular effect can increase renal Na + excretion by elevating pressure in the peritubular capillaries and thereby inhibiting proximal tubule Na + reabsorption (see Chapter 4 ). As a result of these competing effects, AVP may either increase or decrease NaCl excretion. What determines which response predominates is the plasma level of AVP. With low to moderate AVP levels, the V 2 -mediated response predominates and NaCl excretion is decreased. With high AVP levels, the V 1 -mediated response predominates and NaCl excretion is increased. It is important to note that even when NaCl excretion is increased in the setting of high AVP levels, NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct is still stimulated. However, the resorptive capacity of these segments is overwhelmed by the NaCl delivered to these segments from the proximal tubule, and as result, NaCl excretion is increased.
Inadequate release of AVP from the posterior pituitary results in excretion of large volumes of dilute urine ( polyuria ). To compensate for this loss of water, the individual must ingest large volumes of water ( polydipsia ) to maintain constant body fluid osmolality. If the individual is deprived of water, the body fluids become hyperosmotic. This condition is called central diabetes insipidus or pituitary diabetes insipidus. Central diabetes insipidus can be inherited, although this situation is rare. It occurs more commonly after head trauma and with brain neoplasms or infections. Persons with central diabetes insipidus have a urine-concentrating defect that can be corrected by the administration of exogenous AVP.
The inherited (autosomal dominant) form of central diabetes insipidus is caused by a variety of mutations in the AVP gene. In patients with this form of central diabetes insipidus, mutations have been identified in all regions of the AVP gene (i.e., AVP, copeptin, and neurophysin). The most common mutation is found in the neurophysin portion of the gene. In each of these situations, defective trafficking of the peptide occurs, with abnormal accumulation in the endoplasmic reticulum. It is believed that this abnormal accumulation in the endoplasmic reticulum results in death of the AVP secretory cells of the supraoptic and paraventricular nuclei.
The syndrome of inappropriate AVP (ADH) secretion (SIADH) is a common clinical problem characterized by plasma AVP levels that are elevated above what would be expected based on body fluid osmolality and blood volume and pressure—hence the term inappropriate AVP (ADH) secretion. When AVP levels are chronically elevated, the collecting duct overexpresses water channels, thus augmenting the effect of AVP on the kidney. Because not all patients who have inappropriate antidiuresis have elevated AVP levels, the term syndrome of inappropriate antidiuresis (SIAD) is used. Persons with SIADH/SIAD retain water, and their body fluids become progressively hypoosmotic. In addition, their urine is more hyperosmotic than expected based on the low body fluid osmolality. SIADH/SIAD can be caused by infections and neoplasms of the brain, drugs (e.g., antitumor drugs), pulmonary diseases, and carcinoma of the lung. Many of these conditions stimulate AVP secretion by altering neural input to the AVP secretory cells. However, small cell carcinoma of the lung produces and secretes many peptides, including AVP.
Recently, nonpeptide vasopressin receptor antagonists (e.g., conivaptan and tolvaptan) have been developed that can be used to treat SIADH/SIAD and other conditions in which AVP-dependent water retention by the kidneys occurs (e.g., congestive heart failure and hepatic cirrhosis).
In the absence of AVP, the apical membrane of principal cells (see Chapter 2 ), located in the later portion of the distal tubule and along the collecting duct, is relatively impermeable to water. This reflects the fact that in the absence of AVP the apical membrane of these cells contains few water channels ( aquaporins [AQPs] ). Thus, in the absence of AVP, little water is reabsorbed by these nephron segments. Binding of AVP to its cognate receptor (V 2 ) located in the basolateral membrane of principal cells results in the insertion of aquaporin-2 (AQP2) water channels into the apical membrane, allowing water to enter the cell from the tubule lumen. This water then exits the cell across the basolateral membrane, which is always freely permeable to water as a result of the presence of aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels. Thus, in the presence of AVP, water is reabsorbed from the tubule lumen.
AVP also regulates the abundance of AQP2 (and AQP3). When large volumes of water are ingested over an extended period (e.g., psychogenic polydipsia), the abundance of AQP2 and AQP3 in principal cells is reduced. Therefore when water ingestion is restricted, these individuals cannot immediately maximally concentrate their urine. Conversely, in states of restricted water ingestion, AQP2 and AQP3 protein abundance in principal cells increases, thereby facilitating the excretion of maximally concentrated urine.
It is also clear that abundance of AQP2 (and in some instances also AQP3) varies in pathologic conditions associated with disturbances in urine concentration and dilution. AQP2 abundance is reduced in several conditions associated with impaired urine concentrating ability, such as hypercalcemia or hypokalemia. By contrast, in conditions associated with water retention, such as congestive heart failure, hepatic cirrhosis, and pregnancy, AQP2 abundance is increased.
AVP also increases the permeability of the terminal portion of the inner medullary collecting duct to urea. This increase in permeability results in an increase in urea reabsorption and an increase in the osmolality of the medullary interstitial fluid. The inner medullary collecting duct expresses two different urea transporters, UT-A1 and UT-A3. UT-A1 is localized primarily to the apical membrane and UT-A3 is localized primarily to the basolateral membrane. AVP, acting through adenylyl cyclase and the cyclic adenosine monophosphate (cAMP)/protein kinase A cascade, increases the abundance of both UT-1 and UT-3, thus increasing the permeability of this portion of the collecting duct to urea. Increasing the osmolality of the interstitial fluid of the renal medulla also increases the permeability of the collecting duct to urea. This effect is mediated by the phospholipase C/protein kinase C pathway, which also increases UT-1 and UT-3 abundance. This effect is separate from and additive to that of AVP.
AVP also stimulates the reabsorption of NaCl by the thick ascending limb of Henle’s loop and by the distal tubule and collecting duct. This increase in Na + reabsorption is due to an increased abundance of three Na + transporters: 1Na + -1K + -2Cl – symporter (thick ascending limb of Henle’s loop), Na + -Cl – symporter (distal tubule), and Na + channel (epithelial sodium channel [ENaC], in the later portion of the distal tubule and collecting duct). Stimulation of thick ascending limb and collecting duct NaCl transport helps maintain the hyperosmotic medullary interstitium that is necessary for the absorption of water from the medullary portion of the collecting duct (see later).
The gene for the V2 receptor is located on the X chromosome. It codes for a 371-amino-acid protein that is in the family of receptors that have seven membrane-spanning domains and are coupled to heterotrimeric G proteins. As shown in Fig. 5.6 , binding of AVP to its receptor on the basolateral membrane activates adenylyl cyclase. The increase in intracellular cAMP then activates protein kinase A, which results in phosphorylation of AQP2 water channels, which reduces the endocytic removal of AQP2 from the apical membrane and results in increased transcription of the AQP2 gene through activation of a cAMP response element. AVP also increases the rate of insertion of vesicles containing AQP2 into the apical membrane by facilitating their movement along microtubules driven by the molecular motor dynein. Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP2 and facilitate the fusion of these vesicles with the membrane. The net addition of AQP2 to the apical membrane, resulting from reduced endocytosis and increased insertion, allows more water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality). The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels, which are constitutively present in the basolateral membrane. When the V 2 receptor is not occupied by AVP, clathrin-mediated endocytosis of AQP2 is enhanced and the exocytic insertion of AQP2 into the membrane is reduced, which decreases the total number of AQP2 channels in the apical membrane, rendering the apical membrane once again impermeable to water. The endocytosed AQP2 molecules may be either stored in cytoplasmic vesicles, ready for reinsertion into the apical membrane when AVP levels in the plasma increase, or degraded.
Recently individuals have been identified who have activating (gain-of-function) mutations in the V 2 receptor gene. Thus the receptor is constitutively activated even in the absence of AVP. These individuals have laboratory findings like those seen in SIAD, including reduced plasma osmolality, hyponatremia (reduced plasma [Na + ]), and urine more concentrated than would be expected from the reduced body fluid osmolality. In these individuals, plasma levels of AVP are low, and not elevated as seen in more common causes of SIAD where plasma AVP are elevated and thus responsible for the antidiuresis. This form of SIAD has been termed nephrogenic syndrome of inappropriate antidiuresis.
The collecting ducts of some individuals do not respond normally to AVP. These individuals cannot maximally concentrate their urine and consequently have polyuria and polydipsia. This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from several systemic disorders and, more rarely, occurs because of inherited disorders. Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of AQP2 in the collecting duct. Decreased expression of AQP2 has been documented in the urine-concentrating defects associated with hypokalemia, lithium ingestion (some degree of nephrogenic diabetes insipidus develops in 35% of persons who take lithium for bipolar disorder), ureteral obstruction, a low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the AVP receptor (V 2 receptor) gene or the AQP2 gene. Approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V 2 receptor gene, with the other 10% being the result of mutations in the AQP2 gene. Because the gene for the V 2 receptor is located on the X chromosome, these inherited forms are X linked. Most of these mutations result in trapping of the receptor in the endoplasmic reticulum of the cell; only a few cases result in the surface expression of a V 2 receptor that does not bind AVP. The gene coding for AQP2 is located on chromosome 12 and is inherited as both an autosomal recessive and an autosomal dominant defect. As noted in Chapter 1, Chapter 4 , AQPs exist as homotetramers. This homotetramer formation explains the difference between the two forms of nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP2 and defective AQP2 molecules. The defective AQP2 monomer is not delivered to the plasma membrane, and thus the homotetramers that do form contain only normal AQP2 molecules. Accordingly, mutations in both alleles would be required to produce nephrogenic diabetes insipidus. In the autosomal dominant form, the defective monomers can form tetramers with normal monomers, as well as defective monomers. However, these tetramers cannot be delivered to the plasma membrane.
AVP’s primary action on the kidney is to regulate water reabsorption by the collecting duct. However, as noted, AVP also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. This effect of AVP is mediated by activation of the V 2 receptor and is thought to be important in maintaining the hyperosmotic medullary interstitium at a time when AVP is also increasing collecting duct water reabsorption (see later in the chapter). AVP also acts on vascular smooth muscle, via a different receptor (V 1 receptor), causing vasoconstriction and elevating blood pressure. This vascular effect can increase renal Na + excretion by elevating pressure in the peritubular capillaries and thereby inhibiting proximal tubule Na + reabsorption (see Chapter 4 ). As a result of these competing effects, AVP may either increase or decrease NaCl excretion. What determines which response predominates is the plasma level of AVP. With low to moderate AVP levels, the V 2 -mediated response predominates and NaCl excretion is decreased. With high AVP levels, the V 1 -mediated response predominates and NaCl excretion is increased. It is important to note that even when NaCl excretion is increased in the setting of high AVP levels, NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct is still stimulated. However, the resorptive capacity of these segments is overwhelmed by the NaCl delivered to these segments from the proximal tubule, and as result, NaCl excretion is increased.
Inadequate release of AVP from the posterior pituitary results in excretion of large volumes of dilute urine ( polyuria ). To compensate for this loss of water, the individual must ingest large volumes of water ( polydipsia ) to maintain constant body fluid osmolality. If the individual is deprived of water, the body fluids become hyperosmotic. This condition is called central diabetes insipidus or pituitary diabetes insipidus. Central diabetes insipidus can be inherited, although this situation is rare. It occurs more commonly after head trauma and with brain neoplasms or infections. Persons with central diabetes insipidus have a urine-concentrating defect that can be corrected by the administration of exogenous AVP.
The inherited (autosomal dominant) form of central diabetes insipidus is caused by a variety of mutations in the AVP gene. In patients with this form of central diabetes insipidus, mutations have been identified in all regions of the AVP gene (i.e., AVP, copeptin, and neurophysin). The most common mutation is found in the neurophysin portion of the gene. In each of these situations, defective trafficking of the peptide occurs, with abnormal accumulation in the endoplasmic reticulum. It is believed that this abnormal accumulation in the endoplasmic reticulum results in death of the AVP secretory cells of the supraoptic and paraventricular nuclei.
The syndrome of inappropriate AVP (ADH) secretion (SIADH) is a common clinical problem characterized by plasma AVP levels that are elevated above what would be expected based on body fluid osmolality and blood volume and pressure—hence the term inappropriate AVP (ADH) secretion. When AVP levels are chronically elevated, the collecting duct overexpresses water channels, thus augmenting the effect of AVP on the kidney. Because not all patients who have inappropriate antidiuresis have elevated AVP levels, the term syndrome of inappropriate antidiuresis (SIAD) is used. Persons with SIADH/SIAD retain water, and their body fluids become progressively hypoosmotic. In addition, their urine is more hyperosmotic than expected based on the low body fluid osmolality. SIADH/SIAD can be caused by infections and neoplasms of the brain, drugs (e.g., antitumor drugs), pulmonary diseases, and carcinoma of the lung. Many of these conditions stimulate AVP secretion by altering neural input to the AVP secretory cells. However, small cell carcinoma of the lung produces and secretes many peptides, including AVP.
Recently, nonpeptide vasopressin receptor antagonists (e.g., conivaptan and tolvaptan) have been developed that can be used to treat SIADH/SIAD and other conditions in which AVP-dependent water retention by the kidneys occurs (e.g., congestive heart failure and hepatic cirrhosis).
The gene for the V2 receptor is located on the X chromosome. It codes for a 371-amino-acid protein that is in the family of receptors that have seven membrane-spanning domains and are coupled to heterotrimeric G proteins. As shown in Fig. 5.6 , binding of AVP to its receptor on the basolateral membrane activates adenylyl cyclase. The increase in intracellular cAMP then activates protein kinase A, which results in phosphorylation of AQP2 water channels, which reduces the endocytic removal of AQP2 from the apical membrane and results in increased transcription of the AQP2 gene through activation of a cAMP response element. AVP also increases the rate of insertion of vesicles containing AQP2 into the apical membrane by facilitating their movement along microtubules driven by the molecular motor dynein. Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP2 and facilitate the fusion of these vesicles with the membrane. The net addition of AQP2 to the apical membrane, resulting from reduced endocytosis and increased insertion, allows more water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality). The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels, which are constitutively present in the basolateral membrane. When the V 2 receptor is not occupied by AVP, clathrin-mediated endocytosis of AQP2 is enhanced and the exocytic insertion of AQP2 into the membrane is reduced, which decreases the total number of AQP2 channels in the apical membrane, rendering the apical membrane once again impermeable to water. The endocytosed AQP2 molecules may be either stored in cytoplasmic vesicles, ready for reinsertion into the apical membrane when AVP levels in the plasma increase, or degraded.
Recently individuals have been identified who have activating (gain-of-function) mutations in the V 2 receptor gene. Thus the receptor is constitutively activated even in the absence of AVP. These individuals have laboratory findings like those seen in SIAD, including reduced plasma osmolality, hyponatremia (reduced plasma [Na + ]), and urine more concentrated than would be expected from the reduced body fluid osmolality. In these individuals, plasma levels of AVP are low, and not elevated as seen in more common causes of SIAD where plasma AVP are elevated and thus responsible for the antidiuresis. This form of SIAD has been termed nephrogenic syndrome of inappropriate antidiuresis.
The collecting ducts of some individuals do not respond normally to AVP. These individuals cannot maximally concentrate their urine and consequently have polyuria and polydipsia. This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from several systemic disorders and, more rarely, occurs because of inherited disorders. Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of AQP2 in the collecting duct. Decreased expression of AQP2 has been documented in the urine-concentrating defects associated with hypokalemia, lithium ingestion (some degree of nephrogenic diabetes insipidus develops in 35% of persons who take lithium for bipolar disorder), ureteral obstruction, a low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the AVP receptor (V 2 receptor) gene or the AQP2 gene. Approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V 2 receptor gene, with the other 10% being the result of mutations in the AQP2 gene. Because the gene for the V 2 receptor is located on the X chromosome, these inherited forms are X linked. Most of these mutations result in trapping of the receptor in the endoplasmic reticulum of the cell; only a few cases result in the surface expression of a V 2 receptor that does not bind AVP. The gene coding for AQP2 is located on chromosome 12 and is inherited as both an autosomal recessive and an autosomal dominant defect. As noted in Chapter 1, Chapter 4 , AQPs exist as homotetramers. This homotetramer formation explains the difference between the two forms of nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP2 and defective AQP2 molecules. The defective AQP2 monomer is not delivered to the plasma membrane, and thus the homotetramers that do form contain only normal AQP2 molecules. Accordingly, mutations in both alleles would be required to produce nephrogenic diabetes insipidus. In the autosomal dominant form, the defective monomers can form tetramers with normal monomers, as well as defective monomers. However, these tetramers cannot be delivered to the plasma membrane.
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