Hereditary Vasopressin Resistance in Man and Mouse
| Title: | Hereditary Vasopressin Resistance in Man and Mouse |
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| Authors: | Moses, Arnold M.; Scheinman, M.D., Steven J. |
| Publisher: | Annals of the New York Academy of Sciences |
| Date Published: | July 22, 1993 |
| Reference Number: | 128 |
The DI +/+ Severe hereditary nephrogenic diabetes insipidus mouse is resistant to the antidiuretic action of vasopressin (VP) because of failure to accumulate cAMP and subsequent inability to form intramembranous particles on the apical (luminal) surface of kidney cells that normally respond to VP. The defect is primarily, if not exclusively, due to excessive activity of specific cAMP-phosphodiesterases. The abnormality can be overcome in vitro and in vivo by the phosphodiesterase inhibitor, rolipram. Most cases of hereditary NDI in man have sex-linked recessive inheritance, which appears to be due to an abnormality of the V2 receptor. The chromosomal locus of the defect is Xq28. Sporadic cases of congenital NDI have been described in females who appear to have a defect beyond the V2 receptor and the guanine nucleotide-binding stimulatory protein. There is no information on the biochemical defect in very rare cases with other types of inheritance patterns. No abnormalities of V1a and V1b receptor function have been found in patients with NDI. Mice and patients with NDI have evidence of increased AVP synthesis. AVP release in relation to plasma osmolality is increased in patients during infusion of hypertonic saline. This is the opposite of what has been described in patients with primary polydipsia (dipsogenic diabetes insipidus) who are chronically overhydrated. Together, these studies indicate that chronic dehydration and overhydration can cause up- and downregulation of the osmotic release of AVP.
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This is the 100th anniversary of the earliest report we could find that described apparent nephrogenic diabetes insipidus (NDI).1 Dr. McIlraith presented his observations on three generations of a family of patients with polydipsia and hypotonic polyuria who had the classical sex-linked inheritance pattern of hereditary NDI. The present review will describe current knowledge of hereditary NDI in mouse and man, and the effect of this form of chronic dehydration on neurohypophysial function.
In 1964 Falconer et al. described a strain of mice with vasopressin (VP)-resistant impairment of urinary concentration.2 Two abnormal genotypes with severe defects of urinary concentration uncorrectable with vasopressin (VP) have been investigated intensively.2-4 The basic cause of VP resistance in one genotype was found at least in part to be due to a defect in building up the cortico-papillary interstitial osmotic gradient, while the other mice referred to as DI + / + Severe have a decrease in water permeability of the collecting system in response to VP. Some litter mates of DI + / + Severe mice have only a mild concentrating defect and are referred to as DI + / + Nonsevere. Our comments will be limited to the DI + / + Severe mice.3 While control mice are able to concentrate urine to 2800 mOsm/kg in response to VP, DI + / + Severe mice continue to produce hypotonic urine despite supramaximal doses of exogenous AVP.5 Unlike control mice, which can attain osmotic equilibrium between papillary interstitium and the urine, the papillary osmolality in DI + / + Severe mice exceeds urinary osmolality. This indicates that the primary defect in these mice is in VP-induced water permeability of the distal nephron. While papillary osmolality in DI + / + Severe mice is lower than in control mice, this probably results from the high urine flow rate,5 although other factors may be involved (see below). Vascular responsiveness to AVP in the DI + / + Severe mouse is apparently intact.6
The cellular mechanism of resistance to VP in the DI + / + Severe mouse has been studied in detail. The dose of VP required for half-maximal stimulation of adenylate cyclase is not altered, indicating normal receptor affinity for the hormone, but the maximal response is reduced by 40%.5 This blunted response is not a nonspecific consequence of polyuria, since stimulation of adenylate cyclase activity by sodium fluoride or PTH is not altered.5 Early studies using cell-free membrane fractions of the entire renal medulla indicated no abnormality in cAMP-phosphodiesterase (PDE) activity.5 Nevertheless, experiments involving microdissected nephron segments demonstrated a marked increase in cAMP-PDE activity in medullary collecting tubules of these mice.7 The cAMP content of the tubule segments did not increase in response to AVP but did rise if a PDE inhibitor was included.7 More recently, with the advent of highly specific inhibitors of particular isozymes of PDE,8 marked increases have been found in the activity of cAMP-PDE IV, and some increase in cAMP-PDE III, in the inner medullary collecting duct of DI + / + Severe mice.4,6,9,10 Specific inhibition of these isozymes, particularly of cAMP-PDE-IV by the agent rolipram restores the ability of the inner medullary collecting duct to increase its content of cAMP after stimulation by VP. In these studies, the activities of cAMP-PDE were normal.9
Conclusions about VP resistance in water permeability of the collecting system were strengthened by studies of intramembranous particle clusters by the technique of freeze-fracture electron microscopy.11 The incorporation of intramembranous particles into the apical membrane is critical in the biochemical action of VP. This process involves fusion of cytoplasmic vesicles with the apical membrane leading to appearance of clusters of intramembranous particles within that membrane. It is possible that the intramembranous particles constitute specialized channels for the flow of water so that the final event for the action of VP may be the insertion of water-permeable patches into the apical membrane. Harmanci et al. demonstrated a dose-response curve between VP and the frequency of intramembranous particle clusters in Brattleboro rats.12 They noted that the steep portion of the curve representing the cluster frequency falls within the physiological range of the plasma VP concentration (from 1 to 15 pg/ml). The clustering response was subsequently used to gauge the water permeability of collecting ducts in DI + / + Severe mice. These mice showed no clusters whatsoever, even after being treated with large doses of AVP.11 DI + / + Nonsevere animals showed a cluster frequency that fell between that of normal and DI + / + Severe mice. The results strongly supported the concept that a major defect in DI + / + Severe mice is an inability of VP to increase the water permeability of the collecting system. When microdissected inner medullary collecting ducts from DI + / + Severe mice were incubated in the presence of specific inhibitors of cAMP-PDE, AVP normally stimulated both the cAMP response and the formation of IMP clusters.4 Furthermore, administration of cAMP-PDE inhibitors (particularly rolipram) to DI + / + Severe mice in vivo resulted in an improved ability to concentrate the urine.4 Together, these results suggest that excessive activity of cAMP-PDE in the collecting tubule of these mice plays a major role in the resistance to VP.
In addition to modulating the water permeability of the collecting system, VP has at least three other renal actions that aid in the concentration of urine. These include increasing the urea permeability of the terminal portion of the inner medullary collecting duct, stimulating reabsorption of sodium chloride from medullary thick ascending limbs of Henle and indirectly increasing the single nephron glomerular filtration rate mainly of juxtamedullary nephrons. Abnormalities of these mechanisms may contribute to a decrease in the cortico-papillary gradient and aggravate the major defect in DI + / + Severe mice.5
CONGENITAL NEPHROGENIC DIABETES INSIPIDUS IN MAN
The literature on VP-resistant diabetes insipidus in man, extending back to 1923, was reviewed in 1945 by Forssman who added eight cases of his own.13 He found that male-to-male transmission did not occur, that descendants of normal males were healthy, and that polyuria always had its onset in infancy. He also established that female carriers often had mild impairment of urine concentration. Waring, Kajdi, and Tappan expanded the clinical description of the disease the same year on the basis of studies on seven patients in one family.14 These authors stressed the familial and sexual incidence of this disease and characterized it as X-linked recessive. The term nephrogenic to describe this form of DI was introduced by Williams and Henry in 1947.15 Their study of five generations revealed seven cases in males. They confirmed that transmission was recessive and X-linked. Two additional observations were that neither serum nor body cells of patients with hereditary NDI inactivated vasopressin more rapidly than normal and that the injection of Pitressin (AVP) caused a generalized blanching of the skin, abdominal cramps, and increase in blood pressure, even though it did not affect water reabsorption by the kidneys. The classic paper on the Hopewell hypothesis traced the probable geographic origin of most cases of NDI in North America to the Ulster Scots and demonstrated that the defect is due to an X-linked gene with new mutations causing the disorder being "excessively rare."16
Dancis et al. first described the disease in a female and demonstrated that bioassayable antidiuretic substance was present in the urine in significant amounts.17 Since then females with congenital NDI have been described without evident hereditary pattern,18-20 and with autosomal recessive transmission.21 Inn 1984 our group reported data on two women with sporadic congenital NDI with severe polyuria and polydipsia who responded, though subnormally, to desmopressin.19 They were found to be 25 to 50 times as resistant to desmopressin as patients with central DI. Nevertheless, they could be treated effectively with large doses of desmopressin. Other females with sporadic congenital NDI are totally resistant to the antidiuretic action of desmopressin.20 We have found normal V2-like responses to desmopressin in both female patients with severe sporadic NDI whom we have studied (TABLE 1 and see below). One of these women has passed the NDI to her son (V2-like responses not determined).
Families of males and females with congenital NDI have been reported with autosomal dominant22 and with possible sex-linked inheritance patterns.23 No patients with NDI have been described who have been resistant to peptide hormones other than AVP.24 This is in contrast to patients with pseudohypoparathyroidism type 1a who in addition to resistance to PTH do not respond appropriately to TSH, glucagon, and gonadotropins.25 These patients also have impaired olfaction.26 Of particular interest in the present context, however, they are not resistant to the antidiuretic action of VP.27
Our current understanding of the biochemical basis of congenital NDI is primarily derived from studies of the four types of vasopressin receptors that have been functionally identified (TABLE 2). V1b and V2-like receptors differ respectively from V1 and V2 receptors in their different patterns of responsiveness to various V1 and V2 agonists and antagonists.28-31 The only described post-receptor mechanism for the V1b receptor is activation of protein kinase C.32,33 The post-receptor mechanism(s) for the V2-like receptor is unknown.
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Kobrinsky et al. were the first to study the extrarenal effects of the V2 agonist desmopressin in two male patients with hereditary X-linked recessive NDI.34 Circulating levels of factor VIII and von Willebrand antigen failed to increase in either patient and were about 50% of normal in the carriers. In contrast to controls and carriers, facial flushing did not occur in the patients in response to the desmopressin. These authors were thus able to demonstrate that resistance to a V2 agonist in these patients is not confined to the kidney, but also occurs in other tissues including vascular endothelium and hepatic sinusoids. Bichet et al. have measured the responses of mean arterial pressure, pulse rate, factor VIII, and von Willebrand factor to desmopressin in seven male patients with hereditary sex-linked NDI, in six obligatory carriers, and in control subjects.35 In contrast to the controls, who decreased mean arterial pressure and increased pulse rate and circulating coagulant factors in response to desmopressin, the patients with NDI did not respond, and the carriers had only minimal responses. The authors concluded that these patients have an abnormality of the V2-like as well as the V2 receptors. Subsequent studies on three male patients demonstrated that the infusion of epinephrine normally increased circulating levels of clotting factors and cAMP in contrast to the lack of response to desmopressin.36 Since the activity of guanine nucleotide-binding stimulatory protein (Gs) of erythrocyte membranes is normal in patients with hereditary NDI20 (FIG. 1), these observations support an abnormality in these patients of a pre-cAMP mechanism specific for the V2 agonist. This would be analogous to pseudohypoparathyroidism type 1b, which is apparently due to an abnormal PTH receptor.37
| All Three Have Normal V1a Responses and RBC Gs Activity |
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Responses to |
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Age When Studied |
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(mosmol/kg) |
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Responses |
Responses |
Antibodies to AVP |
Conditions |
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congenital NDI |
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Hypertension | |
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Frequent urinary tract infections | |
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Vitiligo | |
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| NOTE: Impaired antidiuretic responses may be due to mutation leading to (1) defect specific of V2 receptor, (2) defect distal to the V2 receptor (or Gs activity). ND = not determined. | ||||||||||
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Responses to V1 and V2 Agonists and Antagonists |
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| Receptor | Post-receptor Mechanisms | Location | Physiological Actions |
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| V1a | Activation of protein kinase C and increase in cytosolic free calcium from stimulation of phospholipase C which causes hydrolysis of phosphatidylinositol | Smooth muscle Hepatocytes Renal medullary interstitial cells Platelet membranes |
Vasoconstriction (includes skin blanching). Contraction of intestinal smooth muscle Glycogenolysis Synthesis and excretion of prostaglandin E2 Platelet aggregation |
| V1b | Activation of protein kinase C | Anterior pituitary | Release of ACTH |
| V2 | Activation of adenylate cyclase and production of cyclic AMP | Renal tubules | Antidiuresis |
| V2-like | Unknown | Vascular endothelium and hepatic sinusoids Vascular smooth muscle |
Release of factor VIII, von Willebrand factor and thromobolytic factors Vasodilatation |
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Our laboratory first reported a heterogeneity in the biochemical cause(s) of congenital NDI in man20 (see A.A., TABLE 1). A male patient who had a probable family history of the disease had no hematologic or vasodilatory responses to desmopressin, while a female with no previous family history of the disease responded normally (FIGS. 2 and 3). The male patient was therefore similar to previously described patients with NDI, while the female patient did not have a generalized desmopressin-sensitive receptor abnormality. Her lack of antidiuretic response could be due to a defect distal to the V2 receptor (and the signal transduction step of adenylate cyclase activation since her Gs activity of erythrocyte membranes was normal) or to a defect of the V2, but not V2-like receptor. Brenner et al. subsequently reported normal hematologic responses to desmopressin in two male and two female patients with congenital NDI.23 Three of these patients, one female and two males, were siblings and members of a family with five affected children. This is the only published evidence of a family with hereditary (possible sex-linked) NDI in whom the V2-like receptor activity was intact (TABLE 3).
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| Figure 2 Plasma levels of factor 8 and von Willebrand factor following intravenous injection of desmopressin (0.4 µg/kg body weight) into two patients with congenital NDI. Patient 1 is a male with possible hereditary sex-linked disease, and patient 2 is a female with sporadic NDI. The latter response is normal (reprinted from Moses et al.20 with permission from the Journal of Clinical Endocrinology and Metabolism). | |
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| Figure 3 Response of plasminogen activator measured by euglobulin clot lysis time in response to desmopressin in the same two patients with NDI as in FIGURE 2. The response of the female patient is normal (reprinted from Moses et al.20 with permission from the Journal of Clinical Endocrinology and Metabolism). |
TABLE 3. Receptor Function in Various Types of Congenital Nephrogenic Diabetes Insipidus | ||||||
Pattern | of Prevalence | V2-Like Receptor Function | Receptor Function | V1b Receptor Function | ||
| X-linked recessive | ||||||
| Sporadic | ||||||
| Familial with unknown inheritance pattern | 2F | |||||
| Autosomal recessive | different locus from X-linked recessive | |||||
| *ND = not determined. | ||||||
TABLE 4. Studies of Hematologic and Vascular Responses to Desmopressin in Patients with Congenital Nephrogenic Diabetes Insipidus | |||||
Normal | Abnormal | Normal | Abnormal | ||
Male | 4 | 26 (87%) | 1 | 3 | |
Female | 3 | 0 | 2 | 0 | |
| NOTE: Most male patients have a V2 and V2-like receptor abnormality, while females have an isolated V2 receptor defect or a post-V2 (and Gs) abnormality causing failure to concentrate the urine. | |||||
Review of published studies and personal observations on hematologic and vascular responses to desmopressin in patients with symptomatic congenital NDI revealed that 26 of 30 males had abnormal hematologic responses and three of four had abnormal vascular responses to desmopressin20,23,34,35,38-41 (TABLE 4). All of the limited number of females studied had normal hematological and vasodilatory responses to desmopressin (TABLE 4). Of the two female patients with normal V2-like responses, one was totally resistant to treatment with desmopressin, and the other responded at 2 to 4% of patients with central DI (TABLE 1). Therefore, the biochemical abnormality in male and female patients (and in hereditary X-linked and sporadic cases of NDI) is apparently different.
The possibility that patients with hereditary X-linked NDI may have excessive phosphodiesterase activity as has been reported in mice with NDI4,6,9,10 was investigated by administering rolipram, a phosphodiesterase inhibitor.42 This medication was ineffective and led the authors to conclude this murine abnormality in cAMP metabolism is probably not present in patients with NDI. These studies have yet to be conducted in female patients where, because of the apparent post-V2 receptor abnormality, the possibility of effectiveness of treatment would be more likely. Since the very recent cloning and characterization of the human V2 receptor gene and the description of its translational product,43,44 several laboratories have been searching actively for a possible mutant gene in patients with NDI. The first report of such an abnormality was based on studies of a kindred of Lithuanian immigrants to the United States who had classical X-linked NDI.45 The investigators found that the patients' DNA from the region of the human V2 receptor gene revealed the insertion of a cytosine residue in the area of the transmembrane domain. This additional cytosine residue shifts the reading frame for protein translation so that the carboxyl terminal 40% of the receptor molecule protein is disrupted by the generation of a meaningless amino acid sequence, and then by premature termination. Results of studies in additional families and in patients with sporadic disease are expected soon. In cases where an abnormality of the V2 receptor is not present, definitive information on biochemical abnormalities will have to await in vitro studies of enzyme kinetics, and so forth, such as have been conducted in the murine model of NDI (see above).
V1a and V1b receptor functions have been normal in all patients with hereditary X-linked recessive NDI who have been studied (TABLE 3). Blanching of the skin and abdominal cramping in response to AVP have been noted from the earliest descriptions of NDI.15,46 These patients increase systemic vascular resistance by constricting arterioles47 and increase urinary prostaglandin E2 excretion normally in response to AVP48 (FIG. 4). Binding of AVP to platelet V1a receptors and induction of platelet aggregation in vitro are normal in males with X-linked hereditary NDI.49 All three females with sporadic congenital NDI increased urinary prostaglandin E2 excretion normally following injection of AVP20,48 (FIG. 4). The V1b receptor on corticotropes28 appears to function normally, because AVP causes an appropriate increase in plasma cortisol in females with sporadic congenital NDI and in males with X-linked hereditary NDI.20,50
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| Figure 4 Values of prostaglandin E2 (PGE2) before and after the subcutaneous injection of 5 IU (12.5 µg) AVP into nine patients with central diabetes insipidus and four patients with NDI. Three of the latter were females with sporadic congenital NDI, and one was a male with possible hereditary NDI. There were no significant differences between patients with central and nephrogenic DI. |
Most cases of human congenital NDI are inherited via X-linkage with variable penetrance in carrier females. More than 20 families of patients with X-linked recessive NDI have been studied using linkage analysis with DNA probes to detect restriction-fragment-length polymorphism.51-53 These studies have localized the gene to the distal part of the long arm of the X-chromosome in the area of the telomere (Xq28). Jans et al. have demonstrated that hamster and mouse somatic lines containing the Xq28 human chromosome fragment all expressed V2 receptor activity.54 Cloning techniques have also localized the human V2 receptor gene in the long arm of the X chromosome close to the locus for hereditary sex-linked NDI.43 These co-mapping studies provide additional evidence that the V2 receptor gene is identical with the NDI locus. The genes responsible for numerous diseases, including hemophilia A, have been localized to the same area. Langley et al. have reported on the only other gene localization studies in patients with hereditary vasopressin-resistant DI.21 In two female patients who had an autosomal mutation, they found that each girl inherited different Xq28 regions of the maternal X chromosomes, ruling out a diagnosis of classical X-linked NDI (TABLE 3).
In the chronic VP-resistant state, there is a constant struggle for water intake to match water losses and chronic mild dehydration results. The hypothalamo-neurohypophysial system of mice with NDI is hypertrophied and hyperplastic and contains more neurosecretory material and VP immunoreactivity than normal controls.55,56 According to Valtin (personal communication), these and other histochemical findings suggest an enhancement of synthesis, storage, and release of AVP, oxytocin, and their neurophysins in the diseased mice. The neural lobes of NDI mice contain normal amounts of vasopressin and oxytocin.57,58
During periods of random hydration, patients with NDI have about a threefold increase in urinary AVP and even during periods of forced overhydration, urinary AVP is in the range of 2.5-5 ng per hour when normal subjects have essentially no AVP in the urine.19, 59 Plasma levels of AVP and its neurophysin as well as platelet fraction AVP are elevated above normal in patients with congenital NDI during random hydration.49 There are no published data on pituitary content of AVP in patients with NDI.
During random hydration, plasma levels of AVP are normal in DI +/+ Severe mice. Nevertheless, AVP levels were much higher in diseased mice when they, as well as the controls, were dehydrated to a similar degree.58
Patients with NDI excrete excessive amounts of AVP in the urine during a defined period of water deprivation.59 Studies of blood levels and urine excretion of AVP in hydrated patients with NDI being infused with 5% saline reveal increased AVP in both plasma and urine (FIGS. 5 and 6). Since AVP is increased in both plasma and urine, it is very likely that patients with NDI have increased AVP release in response to hypertonicity and do not have higher levels of plasma AVP because of a decrease in urinary clearance. This appears to be an example of upregulation of hormone release due to chronic stimulation and is the opposite of the downregulation of AVP release that occurs in patients who are chronically overhydrated owing to primary polydipsia.60 Thus, we have been able to demonstrate that chronic dehydration and overhydration alter the responsiveness of the hypothalamo-neurohypophysial system to hypertonic stimuli.
 Figure 5 Relationship between plasma osmolality and plasma AVP in eleven hydrated normal subjects and four patients with NDI during infusion of 5% saline at 0.05 ml/kg per min. Values were higher in NDI patients using ANOVA (p = 0.04). The rate of rise of AVP was 0.257± 0.012 (SE) pg • ml • mmol • kg in normal subjects and 0.459 ± 0.040 in patients with NDI (p ‹ 0.001). Abscissal intercepts cannot be determined in patients with NDI because plasma AVP concentrations could not be suppressed to undetectable levels (‹ 0.25 pg/ml). |
 Figure 6 Relationship between plasma osmolality and urine AVP under the same conditions as described in FIGURE 5. Values were higher in NDI patients using ANOVA (p ‹ 0.001). The rate of rise of AVP was 24.89 ± 1.76 (SE) pg • min • mmol • kg in normal subjects and 59.55 ± 6.01 in patients with NDI (p ‹ 0.001). As in FIGURE 5, abscissal intercepts cannot be determined in patients with NDI. |
Studies on Long-Evans rats and Brattleboro heterozygous and homozygous rats have been conducted to determine the effect of chronic osmotic stimulation on the transcription of VP and oxytocin genes.61,62 Levels of VP and oxytocin mRNA in magnocellular neurons were found to increase four- to sixfold during two to three days of dehydration or salt loading. The increases in these mRNAs were several-fold greater than the overall increase in expression of ribosomal RNA or the poly(A)-RNA population. The studies were interpreted as upregulation of gene transcription induced by hypertonicity. Studies of this sort in NDI mice are eagerly awaited.
The DI +/+ Severe hereditary nephrogenic diabetes insipidus mouse is resistant to the antidiuretic action of vasopressin (VP) because of failure to accumulate cAMP and subsequent inability to form intramembranous particles on the apical (luminal) surface of kidney cells that normally respond to VP. The defect is primarily, if not exclusively, due to excessive activity of specific cAMP-phosphodiesterases. The abnormality can be overcome in vitro and in vivo by the phosphodiesterase inhibitor, rolipram. Most cases of hereditary NDI in man have sex-linked recessive inheritance, which appears to be due to an abnormality of the V2 receptor. The chromosomal locus of the defect is Xq28. Sporadic cases of congenital NDI have been described in females who appear to have a defect beyond the V2 receptor and the guanine nucleotide-binding stimulatory protein. There is no information on the biochemical defect in very rare cases with other types of inheritance patterns. No abnormalities of V1a and V1b receptor function have been found in patients with NDI. Mice and patients with NDI have evidence of increased AVP synthesis. AVP release in relation to plasma osmolality is increased in patients during infusion of hypertonic saline. This is the opposite of what has been described in patients with primary polydipsia (dipsogenic diabetes insipidus) who are chronically overhydrated. Together, these studies indicate that chronic dehydration and overhydration can cause up- and downregulation of the osmotic release of AVP.
During the four months since the conference in July 1992, several very substantial reports have appeared that describe the V2 receptor abnormality in patients with classical X-linked recessive nephrogenic diabetes insipidus. These abnormalities have been summarized by Davies.63 In brief, he noted and quoted references to nine separate mutations in patients with the disease. He pointed out that mutations in the V2 receptor are clustered in three distinct parts of the molecule--the third transmembrane domain, the third extracellular domain, and the third cytoplasmic loop. The latter mutation causes a frame shift that leads to premature termination of the protein.
In addition, Luzius et al64 have described the molecular basis of nephrogenic diabetes insipidus in a dog family. The kidney inner medulla of the affected dogs possesses normal V2 receptor numbers but with a 10-fold lower affinity for AVP.
- McIRAITH, C. H. 1892. Notes on some cases of diabetes insipidus with marked family and hereditary tendencies. Lancet 2: 767-768.
- FALCONER, D. S., M. LATYSZEWSKI & J. H. ISAACSON. 1964. Diabetes insipidus associated with oligosyndactyly in the mouse. Genet. Res. 5: 473-488.
- NAIK, D. V. & H. VALTIN. 1969. Hereditary vasopressin-resistant urinary concentrating defects in mice. Am. J. Physiol. 217: 1183-1190.
- COFFEY, A. K., D. J. O'SULLIVAN, S. HOMMA, T. P. DOUSA & H. VALTIN. 1991. Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus. Am. J. Physiol. 261: F640-F646.
- VALTIN, H., H. W. Sokol & D. SUNDE. 1975. Genetic approaches to the study of the regulation and actions of vasopressin. Rec. Progr. Horm. Res. 31: 447-486.
- VALTIN, H. 1992. Genetic models of diabetes insipidus. In Handbook of Physiology. Section 8: Renal Physiology. Vol. II: 1281-1316. E. E. Windhager, Ed. Oxford University Press, New York.
- JACKSON, B. A., R. M. EDWARDS, H. VALTIN & T. P. DOUSA. 1980. Cellular action of vasopressin in medullary tubules of mice with hereditary nephrogenic diabetes insipidus. J. Clin, Invest. 66: 110-122.
- BEAVO, J. A. & D. H. REIFSNYDER. 1990. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol. Sci. 11: 150-155.
- HOMMA, S., S. M. GAPSTUR, A. COFFEY, H. VALTIN & T. P. DOUSA. 1991. Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus. Am. J. Physiol. 261: F345-353.
- TAKEDA, S.; C. T. LIN, P. G. MORGANO, S. J. McINTYRE & T. P. DOUSA. 1991. High activity of low-Michaelis-Menten constant 3',5'-cyclic adenosine monophosphate-phosphodiesterase isozymes in renal inner medulla of mice with hereditary nephrogenic diabetes insipidus. Endocrinology 129: 287-294.
- BROWN, D., G. I. SHIELDS, H. VALTIN, J. F. MORRIS & L. ORCI. 1985. Lack of intramembranous particle clusters in collecting ducts of mice with nephrogenic diabetes insipidus. Am. J. Physiol. 249: F582-F589.
- HARMANCI, M. C.; W. A. KACHADORIAN, H. VALTIN & V. A. DISCALA. 1978. Antidiuretic hormone-induced intramembranous alterations in mammalian collecting ducts. Am. J. Physiol. 235: F440-F443.
- FORSSMAN, H. 1945. On hereditary diabetes insipidus with special regard to a sex-linked form. Acta Med. Scand. 121(Suppl. 159): 1-196.
- WARING, A. J., L. KAJDI & V. TAPPAN. 1945. A congenital defect of water metabolism. Am. J. Dis. Child 69: 323-324.
- WILLIAMS, R. H. & C. HENRY. 1947. Nephrogenic diabetes insipidus: Transmitted by females and appearing during infancy in males. Ann. Intern. Med. 27: 84-95.
- BODE, H. H. & J. D. CRAWFORD. 1969. Nephrogenic diabetes insipidus in North America--The Hopewell hypothesis. N. Engl. J. Med. 280: 750-754.
- DANCIS, J., J. R. BIRMINGHAM & S. H. LESLIE. 1949. Congenital diabetes insipidus resistant to treatment with pitressin. Am. J. Dis. Child 75: 316-327.
- SCHREINER, R. L.; P. R. SKAFISH, S. K. ANAND & J. D. NORTHWAY. 1978. Congenital nephrogenic diabetes insipidus in a baby girl. Arch Dis. Child. 53: 906-915.
- MOSES, A. M., S. J. SCHEINMAN & A. OPPENHEIM. 1984. Marked hypotonic polyuria resulting from nephrogenic diabetes insipidus with partial sensitivity to vasopressin. J. Clin. Endocrinol. Metab. 59: 1044-1049.
- MOSES, A. M., J. L. MILLER & M. A. LEVIN. 1988. Two distinct pathophysiological mechanisms in congenital nephrogenic diabetes insipidus. J. Clin. Endocrinol. Metab. 66: 1259-1264.
- LANGLEY, J. M., J. W. BALFE, T. SELANDER, P. N. RAY & J. T. R. CLARKE. 1991. Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus. Am. J. Med. Genet. 38: 90-94.
- OHZEKI, T., T. IGARASHI & A. OKAMOTO. 1984. Familial cases of familial nephrogenic diabetes insipidus type II: Remarkable increment of urinary adenosine 3',5'-monophosphate in response to antidiuretic hormone. J. Pediatr. 104: 593-595.
- BRENNER, B., U. SELIGSOHN & Z. HOCHBERG. 1988. Normal response of factor VIII and von Willebrand factor to 1-desamino-8-D-arginine vasopressin in nephrogenic diabetes insipidus. J. Clin. Endocrinol. Metab. 67: 191-193.
- MOSES, A. M. & B. B. COULSON. 1982. Absence of overlapping resistance to vasopressin and parathyroid hormone in patients with nephrogenic diabetes insipidus and pseudohypoparathyroidism. J. Clin. Endocrinol. Metab. 55: 699-702.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
- modulates the water permeability of the kidneys' collecting system,
- increases the kidneys' urea permeability,
- stimulates sodium chloride reabsorption, and
- increases the kidneys' ability to filter fluids.
There was a strain of mice which was resistant to VP's antidiuretic action. Research found the mice's blunted response to VP occurred because of the strain's failure to accumulate cAMP, an important metabolic regulator. This led to an inability to form membrane particles on the surface of kidney cells that normally respond to VP. This defect primarily occurs because a metabolic regulator called cAMP-phosphodiesterase is too active. The overactivity was modified by injecting the mice with the phosphodiesterase inhibitor, rolipram. And this resulted in improving the mice's ability to concentrate urine.
The literature on NDI in humans dates back to 1923. The first observation determined that NDI was inheritable; that is, it had a genetic basis. Genes are carried in chromosomes within the cell, and the chromosomes can be either sex or non-sex chromosomes. At first, researchers studying family patterns and seeing only males with NDI determined NDI was a recessive trait that was X-linked, that is, the NDI-causing gene was carried on the X chromosome. Later, researchers observed that females could be born with NDI and that the hereditary pattern for NDI females could either be sporadic or a recessive trait linked to an autosomal (non-sex) chromosome. Still later research found families of males and females with congenital NDI (CNDI), and the inheritance patterns were found to be either autosomal dominant or sex-linked. (If a gene is dominant, it only needs itself to come into expression in the offspring, therefore only one parent need carry it in his/her genes. If it is recessive, it needs to be paired with its recessive counterpart, which lives in the cells of the other parent, for it to come into expression in the offspring.)
The understanding of the biochemical basis of congenital NDI was derived from studies of four types of vasopressin receptor genes (V2R). (Vasopressin (VP) is the antidiuretic hormone and V2R is the molecular structure that receives VP's hormonal message.) Researchers observed that males and females with CNDI had different physiological responses to synthetic vasopressin. This indicated that there could be more than one biochemical cause of CNDI. Still, the line of research began to focus on one type of vasopressin receptor gene called vasopressin 2 (V2R), and researchers began looking at possible mutations in V2R that would result in CNDI. The first report on such a mutation came during an investigation of a family with X-linked CNDI. Researchers found the patients' V2R genes had a mutation which resulted in their genetic sequence being cut short and therefore the V2Rs produced by the patients' V2R genes were deprived of their message-receiving capacity.
Worldwide research confirms that most cases of human CNDI are X-linked (i.e., carried on the X chromosome) and appear to be caused by mutations of the V2 receptor gene, which is located on an area of the chromosome known as Xq28. This is the identical location for congenital X-linked NDI.
Other findings: Sporadic cases of CNDI have appeared in females, but the cause does not seem to be a defective V2R. Mice and humans with NDI both synthesize and excrete in their urine the antidiuretic hormone, arginine vasopressin (AVP) in greater amounts than control groups.
Finally, the authors report on the autumn 1992 studies which describe the V2R mutations in patients with X-linked NDI. These mutations are clustered in three distinct parts of the receptor: the third extracellular domain, the third transmembrane domain and the third cytoplasmic loop.