Large-bodied neurons in the paraventricular and supraoptic nuclei of the hypothalamus synthesize AVP, a nonapeptide also known as ADH. These neurons package the AVP and transport it along their axons to the posterior pituitary, where they release AVP through a breech in the blood-brain barrier into the systemic circulation (see pp. 844–845). In Chapter 40, we discuss how increased plasma osmolality and decreased effective circulating volume increase AVP release. AVP has synergistic effects on two target organs. First, at rather high circulating levels, such as those seen in hypovolemic shock, AVP acts on vascular smooth muscle to cause vasoconstriction (see p. 553) and thus to increase blood pressure. Second, and more importantly, AVP acts on the kidney, where it is the major regulator of water excretion. AVP increases water reabsorption by increasing (1) the water permeabilities of the collecting tubules and ducts, (2) NaCl reabsorption in the TAL, and (3) urea reabsorption by the IMCD.
AVP increases water permeability in all nephron segments beyond the DCT
Of the water remaining in the DCT, the kidney reabsorbs a variable fraction in the segments from the ICT to the end of the nephron. Absorption of this final fraction of water is under the control of circulating AVP.
Figure 38-8 summarizes the water permeability of various nephron segments. The water permeability is highest in the proximal tubule and tDLH. The constitutively high water permeability in these segments reflects the abundant presence of AQP1 water channels (see p. 110) in the apical and basolateral cell membranes.
FIGURE 38-8 Water permeability in different nephron segments. Note that the x-axis scale is logarithmic. (Modified from Knepper MA, Rector FC: Urine concentration and dilution. In Brenner BM [ed]: The Kidney. Philadelphia, WB Saunders, 1996, pp 532–570.)
In marked contrast to the proximal tubule and tDLH, the following few segments—from the tALH to the connecting tubule—constitutively have very low water permeabilities. In the absence of AVP, the next tubule segments, the ICT and CCT, have rather low water permeabilities, whereas the MCDs are virtually impermeable to water. However, AVP dramatically increases the water permeabilities of the collecting tubules (ICT and CCT) and ducts (OMCD and IMCD) by causing AQP2 water channels to insert into the apical membrane (see below). A third type of water channel, AQP3, is present in the basolateral cell membranes of MCDs. Like AQP1, AQP3 is insensitive to AVP.
Given the favorable osmotic gradients discussed in the preceding subchapter, high levels of AVP cause substantial water reabsorption to occur in AVP-sensitive nephron segments. In contrast, when circulating levels of AVP are low, for instance after ingestion of large amounts of water, the water permeability of these nephron segments remains low. Therefore, the fluid leaving the DCT remains hypo-osmotic as it flows down more distal nephron segments. In fact, in the absence of AVP, continued NaCl absorption makes the tubule fluid even more hypo-osmotic, which results in a large volume of dilute urine (see Fig. 38-1).
AVP, via cAMP, causes vesicles containing AQP2 to fuse with apical membranes of principal cells of collecting tubules and ducts
AVP binds to V2 receptors in the basolateral membrane of the principal cells from the ICT to the end of the nephron (Fig. 38-9). Receptor binding activates the Gs heterotrimeric G protein, stimulating adenylyl cyclase to generate cAMP (see pp. 56–57). The latter activates protein kinase A, which phosphorylates AQP2 and additional proteins that play a role in the trafficking of intracellular vesicles containing AQP2 and the fusion of these vesicles with the apical membrane. These water channels are AVP sensitive, not in the sense that AVP increases their single channel water conductance, but rather that it increases their density in the apical membrane. N38-6 In conditions of low AVP, AQP2 water channels are mainly in the membrane of intracellular vesicles just beneath the apical membrane. In the membrane of these vesicles, the AQP2 water channels are present as aggregophores—aggregates of AQP2 proteins. Under the influence of AVP, the vesicles containing AQP2 move to the apical membrane of principal cells of the collecting tubules and ducts. By exocytosis (see pp. 34–35), these vesicles fuse with the apical membrane, thus increasing the density of AQP2. When AVP levels in the blood decline, endocytosis retrieves the water channel–containing aggregates from the apical membrane and shuttles them back to the cytoplasmic vesicle pool.
FIGURE 38-9 Cellular mechanism of AVP action in the collecting tubules and ducts. AC, adenylyl cyclase; AP1, activator protein 1; CRE, cAMP response element.
Multiple Effects of Arginine Vasopressin on AQP2 Activity
Contributed by Erich Windhager, Gerhard Giebisch
On page 818, we mentioned that AVP acts through cAMP and protein kinase A (PKA) to phosphorylate AQP2 and other proteins. One result of these phosphorylation events is to increase the trafficking of AQP2 from vesicular pools to the apical membrane of the collecting-duct cells. Thus, AVP increases AQP2 density in the apical membrane; that is, the number of water channels per unit area of apical membrane.
In addition, PKA also phosphorylates AQP2 itself as well as cAMP response element–binding protein (CREB; see p. 89). The phosphorylation of CREB, in the longer term, stimulates AQP2 synthesis, as indicated in Figure 38-9.
The apical water permeability of principal cells depends not only on AVP levels but also on certain other factors. For example, high [Ca2+]i and high [Li+] both inhibit adenylyl cyclase, thus decreasing [cAMP]i, reducing water permeability, and producing a diuresis. A similar inhibition of AQP2 insertion, and hence a decrease in water permeability, occurs when agents such as colchicine disrupt the integrity of the cytoskeleton. Conversely, inhibitors of phosphodiesterase (e.g., theophylline), which increase [cAMP]i, tend to increase the osmotic water permeability. In addition to regulating AQP2 trafficking in and out of the apical membrane in the short term, AVP regulates AQP2 protein abundance over the longer term.
AVP increases NaCl reabsorption in the outer medulla and urea reabsorption in the IMCD, enhancing urinary concentrating ability
AVP promotes water reabsorption not only by increasing the water permeability of the collecting tubules and ducts, but also by enhancing the osmotic gradients across the walls of the IMCD and perhaps the OMCD. In the outer medulla, AVP acts through the cAMP pathway to increase NaCl reabsorption by the TAL. AVP acts by stimulating apical Na/K/Cl cotransport and K+ recycling across the apical membrane (see p. 768). The net effect is to increase the osmolality of the outer medullary interstitium and thus enhance the osmotic gradient favoring water reabsorption by the OMCD. In addition, AVP stimulates the growth of TAL cells in animals that are genetically devoid of AVP. This hormone also stimulates Na+ reabsorption in the CCT, largely by activating apical Na+ channels (ENaCs). These observations on the TAL and CCT were all made on rodents. In humans these TAL and CCT mechanisms may have only minor significance.
In the inner medulla, AVP enhances the urea permeability of the terminal two thirds of the IMCD (see pp. 811–813). The AVP-dependent increase in [cAMP]i that triggers the apical insertion of AQP2-containing vesicles also leads to a phosphorylation of apical UT-A1 and basolateral UT-A3 urea transporters (see p. 770), increasing their activity. The result is a substantial increase in urea reabsorption and thus the high interstitial [urea] that is indirectly responsible (see p. 816) for generating the osmotic gradient that drives water reabsorption in the inner medulla (Boxes 38-1, 38-2, and 38-3).
Diabetes insipidus (DI) is a fairly rare disorder that occurs in two varieties. The first, neurogenic or central DI, is caused by failure of AVP secretion. The lesion can be at the level of either the hypothalamus (where neurons synthesize AVP) or the pituitary gland (where neurons release AVP). Central DI can be idiopathic, familial, or caused by any disorder of the hypothalamus or pituitary, such as injury, a tumor, infection, or autoimmune processes. In the second variety, nephrogenic DI (NDI), the kidneys respond inadequately to normal or even elevated levels of circulating AVP due to familial or acquired defects. Ninety percent of the familial cases are due to mutations in the X-linked AVPR2 gene that encodes the V2 receptor, and 10%, to mutations in the AQP2 gene. Acquired NDI may be associated with electrolyte abnormalities (e.g., states of K+ depletion or high plasma [Ca2+] N36-14), the renal disease associated with sickle cell anemia, and various drugs (notably Li+ salts and colchicine).
In both central and nephrogenic DI, patients present with polyuria and polydipsia. If patients cannot gain access to water on their own (e.g., infants, bedridden elderly), the disorder can result in marked hypernatremia, hypotension, and shock. Often the physician first suspects the diagnosis when the patient is deprived of access to water or other fluids. The patient may then quickly become dehydrated, and a random determination of plasma [Na+] may yield a very high value.
The physician can confirm the diagnosis of DI most easily by a fluid-deprivation test. The patient will continue to produce a large output of dilute urine, despite the need to conserve fluids. If the patient has central DI, administering a subcutaneous dose of AVP will rapidly increase urine osmolality by >50%. In patients with nephrogenic DI, on the other hand, the increase in urine osmolality will be less.
The treatment for central DI is desmopressin acetate (DDAVP) (see Fig. 56-10), a synthetic AVP analog that patients can take intranasally. Nephrogenic DI, in which the kidneys are resistant to the effects of the hormone, does not respond to DDAVP therapy. In these patients, it is best to treat the underlying disease. It can also be helpful to administer a diuretic (to produce natriuresis) and restrict dietary Na+ to induce a state of volume depletion, which in turn enhances proximal NaCl and water reabsorption and thereby moderates the polyuria.
The high urine flow in DI is associated with low rates of solute excretion. Therefore, the physician must distinguish DI from states of polyuria accompanied by high rates of solute excretion in the urine (osmotic diuresis). The most frequent cause of the latter is untreated diabetes mellitus. In that case, the polyuria occurs because the high plasma [glucose] leads to the filtration of an amount of glucose that exceeds the capacity of the proximal tubule to retrieve it from the lumen (see pp. 772–773). Another cause of osmotic diuresis is the administration of poorly reabsorbable solutes, such as mannitol.
In an entirely distinct class of polyurias is primary polydipsia, a psychoneurotic disorder in which patients drink large amounts of fluid. Whereas simple water deprivation benefits a patient with primary polydipsia, it aggravates the condition of a patient with DI.
Role of Aquaporins in Renal Water Transport
Whereas AQP1 is the water channel responsible for a large amount of transcellular fluid movement in the proximal tubule and the tDLH, three related isoforms of the water channel protein—AQP2, AQP3, and AQP4—are present in the principal cells of the collecting ducts. These channels regulate water transport in collecting tubules and ducts. Apical AQP2 is the basis for AVP-regulated water permeability. AQP3 and AQP4 are present in the basolateral membrane of principal cells, where they provide an exit pathway for water movement into the peritubular fluid.
Short-term and long-term regulation of water permeability depends on an intact AQP2 system. In short-term regulation, AVP—via cAMP—causes water channel–containing vesicles from a subapical pool to fuse with the apical membrane (see Fig. 38-9). As a result, the number of channels and the water permeability sharply increase. In long-term regulation, AVP—by enhancing transcription of the AQP2 gene—increases the abundance of AQP2 protein in principal cells.
Mutations of several AQP genes lead to loss of function and marked abnormalities of water balance. Examples include sharply decreased fluid absorption along the proximal tubule in AQP1 knockout animals and nephrogenic diabetes insipidus (see Box 38-1) in patients with mutations of the gene for AQP2. An interesting situation may develop during the third trimester of pregnancy, when elevated plasma levels of vasopressinase—a placental aminopeptidase that degrades AVP—may lead to a clinical picture of central diabetes insipidus.
An acquired increase of AQP2 expression often accompanies states of abnormal fluid retention, such as congestive heart failure, hepatic cirrhosis, nephrotic syndrome, and pregnancy. In addition, some conditions—including acute and chronic renal failure, primary polydipsia, consumption of a low-protein diet, and syndrome of inappropriate antidiuretic hormone secretion (see Box 38-3)—are associated with increased AQP2 levels in the apical membrane.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
The syndrome of inappropriate ADH secretion (SIADH) is the opposite of diabetes insipidus. Patients with SIADH secrete ADH (i.e., AVP) or AVP-like substances at levels that are inappropriately high, given the low plasma osmolality and lack of hypovolemia. Thus, the urine osmolality is inappropriately high and patients are unable to excrete ingested water loads normally. As a result, total-body water increases, the blood becomes hypo-osmolar, plasma [Na+] drops (hyponatremia), and cells swell. If plasma [Na+] falls substantially, cell swelling can cause headaches, nausea, vomiting, and behavioral changes. Eventually, stupor, coma, and seizures may ensue.
Before making the diagnosis of SIADH, the physician must rule out other causes of hyponatremia in which AVP levels may be appropriate. In Chapter 40, we discuss how plasma osmolality (see p. 844) and effective circulating volume (see p. 843) appropriately regulate AVP secretion. SIADH has four major causes:
1. Certain malignant tumors (e.g., bronchogenic carcinoma, sarcomas, lymphomas, and leukemias) release AVP or AVP-like substances.
2. Cranial disorders (e.g., head trauma, meningitis, and brain abscesses) can increase AVP release.
3. Nonmalignant pulmonary disorders (e.g., tuberculosis, pneumonia, and abscesses) and positive-pressure ventilation also can cause SIADH. N38-7
4. Several drugs can either stimulate AVP release (e.g., clofibrate, phenothiazines), increase the sensitivity of renal tubules to AVP (e.g., chlorpropamide), or both (e.g., carbamazepine).
Treatment is best directed at the underlying disorder, combined, if necessary and clinically appropriate, with fluid restriction. Patients with severe hyponatremia and marked symptoms must receive urgent attention. Infusion of hyperosmotic Na+ is usually effective, but the correction must be gradual or severe neurological damage can result owing to rapid changes in the volume of neurons, especially in the pontine area of the brainstem.
Pulmonary Disorders Causing Syndrome of Inappropriate Antidiuretic Hormone Secretion
Contributed by Emile Boulpaep, Walter Boron
Several chronic, nonmalignant pulmonary conditions, including positive-pressure ventilation, impede venous return. The result is reduced stretch of the atrial receptors (see Fig. 23-7). As discussed on page 547, the afferent fibers from these stretch receptors project not only to the medulla (where they produce cardiovascular effects) but also to the hypothalamic neurons that synthesize and release AVP. Decreased atrial stretch increases AVP release. Thus, the aforementioned pulmonary conditions result in a syndrome of inappropriate AVP (ADH) release—SIADH.