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Genetic Models of Diabetes Insipidus

Heinz Valtin

10.1002/cphy.cp080228

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Classification of Diabetes Insipidus
2 Hypothalamic Diabetes Insipidus
2.1 History of the Brattleboro Rat
2.2 Biosynthesis of Vasopressin
2.3 Pathophysiology of Hypothalamic Diabetes Insipidus
3 Nephrogenic Diabetes Insipidus
3.1 Description of Mouse Strains
3.2 Causes: Corticopapillary Gradient vs. Water Permeability
3.3 Defects in the Mouse Strains
3.4 Pathophysiology of Nephrogenic Diabetes Insipidus
4 Other Applications of the Models
4.1 Amount of Water Reabsorbed from Collecting Ducts
4.2 The Running Start
4.3 Hyponatremia during Sodium Depletion
4.4 Essentiality of Vasopressin
5 Use of Both Models Simultaneously
5.1 Nephron Heterogeneity
5.2 Innervation of Vasopressin Neurons
5.3 Alcohol Preference
6 Summary and Concluding Remarks
Figure 1. Figure 1.

A. One of Verney's trained dogs, Pat. Exteriorized loops of common carotid arteries appear in front of rectangular piece of black paper. B. Summary of some important results obtained by E. B. Verney on unanesthetized dogs. Solid line graph represents results prior to removal of the neurohypophysis; dashed line shows results on same animal after neurohypophysectomy. p.o., per os (by mouth); i.a., intraarterially (into the exteriorized loop of the common carotid artery); i.v., intravenously. C. Schema proposed by Verney, whereby changes in plasma osmolality regulate the secretion of antidiuretic hormone (ADH, or vasopressin), and hence of urinary flow and osmolality. D. Water‐deprivation test for differentiating major types of diabetes insipidus. The rationale for designating each type of the appropriate adjectives is given in the text.

Figs. 1B, C, D slightly modified from Valtin 174. From Verney 190
Figure 2. Figure 2.

Phenotypic characteristics of normal rats of the Long‐Evans hooded strain, of Brattleboro heterozygotes, and of Brattleboro homozygotes. Bars and brackets denote means ± SEM. Asterisks indicate values that are significantly different from those in Long‐Evans normal rats (P < 0.05). Data from 183.

From Valtin 171
Figure 3. Figure 3.

A. Neural lobe contents of vasopressin and oxytocin (graph at top), and of their associated neurophysins (graph at bottom), in Long‐Evans normal rats, Brattleboro heterozygotes, and Brattleboro homozygotes. VP‐RNP and VP‐RNP', vasopressin‐associated rat neurophysins; OT‐RNP, OT‐RNP', and OT‐RNP', oxytocin‐associated rat neurophysins. B. Structure of bovine preprovasopressin. AA, amino acid residues; CHO, carbohydrate moiety, which attaches to the future glycopeptide at an asparagine residue in position 6. The structure of preprovasopressin from rats is identical except that the signal peptide contains 23 amino acids and the neurophysin 93 amino acids, with threonine instead of valine at the C‐terminus.

Adapted from North 113. From Valtin et al. 182
Figure 4. Figure 4.

A. Part of neurohypophysis from a Brattleboro homozygous rat. Large axonal swelling, marked S, is filled with normal neurosecretory granules that presumably contain oxytocin. The same is true of two axonal endings, marked E. In contrast, axonal ending marked EA, in the upper left portion of the section, lacks normal neurosecretory granules and is filled instead with smaller granules. Presumably, EA endings in Brattleboro homozygotes represent the abnormal neurons whose counterparts in normal rats would produce vasopressin. B. Typical electrical recordings, in rats, from an oxytocin‐producing neuron, which has been stimulated by suckling, and from a vasopressin‐producing neuron, which has been stimulated by hemorrhage (HAEM). Both neurons were located in the supraoptic nucleus (SO). The oxytocin cell showed a characteristic burst by firing just prior to releasing oxytocin, as reflected by an increase in intramammary pressure (milk ejection). In contrast, the vasopressin cell showed prolonged, phasic increase in firing rate when 5 ml of blood was removed (HAEM). OT, optic tract. C. Production of vasopressin in a specific neuron of the hypothalamoneurohypophysial system (see text). Oxytocin is produced in an analogous manner in a separate set of cells, except that prooxytocin is not glycosylated. The perikarya of each cell type are found in both the supraoptic and paraventricular nuclei (see Table 1)

From Dyball et al. 38. Modified from Valtin et al. 182. From Morris et al. 109
Figure 5. Figure 5.

A. Normal and mutant genes that encode for the vasopressin precursor (preprovasopressin) in normal rats (Long‐Evans and Wistar strains) and Brattleboro rats, respectively. The arrowheads indicate the deletion of the guanosine nucleotide in the Brattleboro gene and the consequent carboxy terminus of the mutant preprovasopressin (hatched rectangle). CP‐14 is an abnormal 14‐amino acid peptide, which was used for immunocytochemical studies. SP, signal peptide; AVP, arginine vasopressin; NP, neurophysin; GP, glycopeptide; CHO, site of glycosylation. [Slightly modified from Guldenaar et al. 56.] B. Comparisons of mRNAs and the predicted vasopressin precursors in: hypothalamus of normal rats (top); hypothalamus of Brattleboro rats (middle); and adrenal glands and ovaries of Brattleboro rats (bottom). Abbreviations and symbols as given above. Because a stop condon is lacking in the mutant mRNA, its poly (A) sequence is translated in the Brattleboro rat; the resulting polylysine tail is very long in the hypothalamus but relatively short in other organs.

Slightly modified from Ivell et al. 76
Figure 6. Figure 6.

A. Characteristics of normal VII +/+ mice and of four strains of mice with nephrogenic defects of urinary concentration. The open bars indicate urine osmolalities while the mice were eating and drinking at will, and the hatched bars the urine osmolalities after 3 consecutive days of treatment with Pitressin tannate in oil (ADH), 0.25 unit/day given subcutaneously. All values are mean ± SEM; asterisks indicate values that are significantly different from those in VII +/+ animals. b wt, body weight; BUN, blood urea nitrogen. B. Urine osmolalities in DI +/+ Severe and DI +/+ Nonsevere mice eating and drinking at will, plotted as a function of age. The same mice were tested at different ages, although a single mouse was not necessarily examined over the entire time span. Each circle or dot represents the mean of as many as 17 or as few as 2 mice (average, 10 animals). C. Osmolalities of urine (large symbols) and papillary tips (small symbols) in normal VII +/+ mice, and four strains with vasopressin‐resistant defects of urinary concentration. Origin of each line represents the cortical interstitial osmolality; slope of each line, the corticopapillary gradient in that particular strain. Values are means ± SEM.

From Kettyle and Valtin 84. Adapted from Naik and Valtin 112. From Valtin 170
Figure 7. Figure 7.

A. Cascade of events whereby vasopressin is thought to increase water permeability of responsive cells. Reaction involves the V2 receptor for vasopressin. The example given here, which pertains to principal cells of the mammalian collecting duct, is based partly on data obtained in anuran membranes. Uninterrupted arrows denote steps that have been defined; interrupted arrows with question marks, postulated steps. ADH, antidiuretic hormone, or vasopressin; s, stimulatory guanine nucleotide regulatory protein; ATP, adenosine triphosphate; cAMP, cyclic 3′,5′‐adenosine monophosphate; S'AMP, adenosine 5'‐monophosphate; cAMP‐PDE, cyclic AMP phosphodiesterase; IMPs, intramembranous particles. The same cascade initiated through the V2 receptor is thought to be responsible for two other effects of vasopressin, namely, an increase in urea permeability of inner medullary collecting ducts, and an augmentation of NaCl transport in medullary thick ascending limbs of Henle (see Fig. 10A). B, C. Freeze‐fracture replicas of apical (luminal) membranes of principal cells from inner medullary collecting ducts of homozygous Brattleboro rats before (B) and after (C) treatment with vasopressin. In the absence of vasopressin (B), no clusters of intramembranous particles can be seen, whereas in the presence of the hormone (C), there are many such clusters (indicated by arrows). The larger depressions represent microvilli. Shadowing directions are indicated by the arrowheads. Bar = 0.5 μm. D. Relationship between rate of vasopressin infusion in Brattleboro homozygotes and the frequency of intramembranous particle clusters in the apical (luminal) membranes of their collecting ducts. Steep portion of the curve spans physiological range of plasma vasopressin concentration.

From Harmanci et al. 63 From Harmanci et al. 62
Figure 8. Figure 8.

Percentage of collecting duct cells showing clusters of intramembranous particles (IMP) and concurrent urinary osmolalities in normal (VII +/+) mice and in two genotypes with mild (DI +/+ Nonsevere) and marked (DI +/+ Severe) nephrogenic defects of urinary concentration. The cells examined were principal cells from inner medullary collecting ducts. Five of the eight DI +/+ Severe mice were pretreated with large doses of the vasopressin analogue, 1‐desamino‐8‐D‐arginine vasopressin (dDAVP). *, significantly different from VII +/+; †, significantly different from DI +/+ Nonsevere.

From Brown et al. 18
Figure 9. Figure 9.

Aspects of cyclic 3′,5′‐adenosine monophosphate (cAMP) metabolism in collecting ducts of VII +/+ (normal) and DI +/+ Severe mice. Collecting ducts were dissected from the inner stripe of the outer medulla. A. Content of cAMP during basal (B) conditions and after a 20‐min exposure to 10−6 M arginine vasopressin (AVP). Each column and bracket represents the mean ± SEM of 14–15 tubular samples obtained from each of five VII +/+ and five DI +/+ Severe mice. NS, not significant. The difference in basal levels between the two strains was statistically significant, with a P value of < 0.01. B. Activity of cAMP phosphodiesterase (cAMP‐PDE). Columns and brackets represent means ± SEM of five animals in each strain. The difference between the two values was statistically significant, as indicated by a P value of < 0.05. Increased activity of cAMP‐PDE has been demonstrated as well in cortical and inner medullary collecting ducts of DI +/+ Severe mice 49,73. C. Stimulation of adenylate cyclase by a maximal concentration (10−6 M) of arginine vasopressin (AVP). The columns and brackets represent the mean ± SEM of four to six tubular samples obtained from each of four VII +/+ and four DI +/+ Severe animals. While there was not a significant difference in the basal activities (B), the vasopressin‐stimulated activity was significantly lower in DI +/+ Severe than in VII +/+ animals, as indicated by the P value of < 0.005. This difference, however, was no longer apparent when the results were expressed per mm tubule length rather than per unit of protein (see Table III of reference 77), nor was the difference present in inner medullary collecting ducts (Homma et al., unpublished data).

A, B, C from Jackson et al. 77
Figure 10. Figure 10.

A. Locations and actions within the nephron where vasopressin acts to abet the concentration of urine: (1) increased water permeability of the collecting system; (2) increased urea permeability of the final portion of inner medullary collecting ducts; (3) increased reabsorption of NaCl from medullary thick ascending limbs of Henle; and (4) increased glomerular filtration rate in juxtamedullary nephrons. The first three actions are mediated via V2 receptors; the last is probably an indirect effect (see text). md, macula densa. B. Filtration rates in single glomeruli of outer cortical (OC) and juxtamedullary (JM) nephrons in: Brattleboro heterozygous rats (heteros), which have endogenous vasopressin; Brattleboro homozygotes (homos), which lack the hormone; and Brattleboro homozygotes treated with the vasopressin analog l‐desamino‐8‐D‐arginine vasopressin (dDAVP). Symbols represent mean ± SEM. C, D. Aspects of cyclic 3′,5′‐adenosine monophosphate (cAMP) metabolism in medullary thick ascending limbs of Henle of VII +/+ (normal) and DI +/+ Severe mice. The thick ascending limbs were dissected from the inner stripe of the outer medulla. As shown in C, both basal (B) and vasopressin‐stimulated (AVP, 10−6 M) activation of adenylate cyclase were significantly lower in DI +/+ Severe than in VII +/+ animals. There were, however, no significant differences in the activity of cAMP‐phosphodiestcrase (cAMP‐PDE) (D). Each column and bracket represents the mean ± SEM of four to six tubular samples obtained from each of four or five animals. *, significantly lower (P < 0.02) than basal activity (B) in VII +/+ mice; NS, not significant. E. Ratio of the glomerular filtration rate in single juxtamedullary nephrons to the filtration rate in single outer cortical nephrons. In this study, DI +/+ Nonsevere mice served as controls in the sense that, unlike DI +/+ Severe animals, they can render their urine hypertonic to plasma (Fig. 6A) and therefore can respond to vasopressin, at least partially. Bars and brackets denote mean ± SEM; the asterisk reflects a value that is significantly different from DI +/+ Nonsevere mice (P < 0.05). F. Aortic pressure in DI +/+ Severe mice in response to a large intravenous bolus of synthetic aqueous arginine vasopressin (AVP). The heavy line shows the mean response for the five mice. Uosm, urine osmolality.

From Veal and Valtin, unpublished data. Adapted from Valtin 177. Adapted from Trinh et al. 166, and reprinted from Valtin 178. From Jackson et al. 77. Adapted from Trinh et al. 167
Figure 11. Figure 11.

A, B. An experiment in a Brattleboro homozygous rat, which showed that the amount of water reabsorbed from the terminal collecting duct is actually greater during water diuresis (A) than during antidiuresis (B). Each diagram portrays the tip of the papilla in the same rat, before it received vasopressin and after an intravenous infusion of the hormone. Details described in text. The hairpin structure represents a long loop of Henle, and it shows that vasopressin increased the papillary interstitial osmolality from approximately 550 to 925 mOsm/kg H2O. The branched structure is the final ∼ 1 mm of a collecting duct. TF/P osm, ratio of osmolality in tubular fluid to that in plasma; P/TF in, ratio of inulin concentration in plasma to that in tubular fluid. C. Summary of the findings in 18 Brattleboro homozygous rats. Bars and brackets = mean ± SEM.

Slightly modified from Jamison et al. 78
Figure 12. Figure 12.

A. Proportions of the filtered load of water that are reabsorbed in various parts of the nephron during antidiuresis. Unless these approximate amounts are reabsorbed before tubular fluid enters the medullary collecting ducts, the ability to render the urine hyperosmotic to plasma will be curtailed or abolished. B. Inverse correlation, in rats, between the urinary flow immediately before giving vasopressin and the subsequent ability of the kidneys to concentrate urine in response to a very high dose of the hormone (1.0 unit Pitressin tannate in oil, subcutaneously, per rat). Each point represents one animal. For all 45 observations, the correlation coefficient is −0.902. It should be emphasized that this graph is not simply a plot of urinary flow and osmolality in the same sample. Rather, each point represents the flow and osmolality, respectively, during two successive 24 h periods.

From Valtin and Harrington 180
Figure 13. Figure 13.

A. Changes in sodium and water balance in a healthy adult human during sodium chloride depletion (days 1 through 11) and repletion (days 12 through 16). Each vertical arrow denotes a 2 h period that the subject spent in a sweat box. PNa+, plasma sodium concentration. Details described in text. B. Development of hyponatremia during sodium chloride depletion in eight Brattleboro homozygotes, which lack vasopressin, and seven control rats (Brattleboro heterozygotes) that have vasopressin. The serum sodium concentration is known to be higher in Brattleboro homozygotes than in control rats 184; this fact, however, cannot be attributed simply to contraction of the body fluid volumes 50,123. C. Schematic representation of the proposal by Berliner and Davidson 11, whereby the kidneys can retain solute‐free water in the absence of vasopressin. Details given in text.

Adapted from Valtin 174. Adapted from Mc‐Cance 103. Adapted from Harrington 64
Figure 14. Figure 14.

Diagrams summarizing quantitative analysis of the relationship between vasopressin‐producing cell bodies (large dots) in the supraoptic nucleus and their innervation by catecholamine varicosities (small dots). Hypertrophy and increased staining density of the vasopressin‐producing perikarya in the DI Os/ + mice accompanied by a marked increase in the catecholamine varicosities. The four diagrams for each mouse model represent sections at four levels of the supraoptic nucleus, progressing from the rostral (optic chiasm) to the caudal (optic tract) end of the nucleus.

Slightly modified from Davis et al. 32
Figure 15. Figure 15.

A. Preference scores for drinking 2.2% ethanol solution or tap water, and simultaneous total daily fluid intake, in three types of experimental animals: Brattleboro rats; Roman High Avoidance rats (RHA); and mice with nephrogenic defects of urinary concentration. Open columns denote control values; hatched columns, values during high fluid turnover; and crosshatched columns, values during ameliorated fluid turnover. Rationale and interpretation of each experiment are described in the text. Heteros, Homos, Brattleboro heterozygotes and homozygotes, respectively; LVP, lysine vasopressin; RHA +/+, Roman High Avoidance rats lacking the Brattleboro gene; RHA di/di, Roman High Avoidance rats homozygous for the Brattleboro gene; dGAVP, desglycinamide9‐arginine8‐vasopressin; DI + /+ Nonsevere and DI Os/ +, mice with a nephrogenic defect of urinary concentration and with nephrogenic diabetes insipidus, respectively (see Fig. 6). Asterisks denote values that are significantly different from those in animals with high fluid turnover. [Data from Rigter and Crabbe 31,121.] B. Inverse relationship between the total fluid intakes of DI Os/+ mice and their preference scores for drinking 2.2% ethanol solution or tap water. Each point represents one DI Os/+ mouse. The correlation coefficient for this plot is −0.75.

Slightly modified from Crabbe and Rigter 31


Figure 1.

A. One of Verney's trained dogs, Pat. Exteriorized loops of common carotid arteries appear in front of rectangular piece of black paper. B. Summary of some important results obtained by E. B. Verney on unanesthetized dogs. Solid line graph represents results prior to removal of the neurohypophysis; dashed line shows results on same animal after neurohypophysectomy. p.o., per os (by mouth); i.a., intraarterially (into the exteriorized loop of the common carotid artery); i.v., intravenously. C. Schema proposed by Verney, whereby changes in plasma osmolality regulate the secretion of antidiuretic hormone (ADH, or vasopressin), and hence of urinary flow and osmolality. D. Water‐deprivation test for differentiating major types of diabetes insipidus. The rationale for designating each type of the appropriate adjectives is given in the text.

Figs. 1B, C, D slightly modified from Valtin 174. From Verney 190


Figure 2.

Phenotypic characteristics of normal rats of the Long‐Evans hooded strain, of Brattleboro heterozygotes, and of Brattleboro homozygotes. Bars and brackets denote means ± SEM. Asterisks indicate values that are significantly different from those in Long‐Evans normal rats (P < 0.05). Data from 183.

From Valtin 171


Figure 3.

A. Neural lobe contents of vasopressin and oxytocin (graph at top), and of their associated neurophysins (graph at bottom), in Long‐Evans normal rats, Brattleboro heterozygotes, and Brattleboro homozygotes. VP‐RNP and VP‐RNP', vasopressin‐associated rat neurophysins; OT‐RNP, OT‐RNP', and OT‐RNP', oxytocin‐associated rat neurophysins. B. Structure of bovine preprovasopressin. AA, amino acid residues; CHO, carbohydrate moiety, which attaches to the future glycopeptide at an asparagine residue in position 6. The structure of preprovasopressin from rats is identical except that the signal peptide contains 23 amino acids and the neurophysin 93 amino acids, with threonine instead of valine at the C‐terminus.

Adapted from North 113. From Valtin et al. 182


Figure 4.

A. Part of neurohypophysis from a Brattleboro homozygous rat. Large axonal swelling, marked S, is filled with normal neurosecretory granules that presumably contain oxytocin. The same is true of two axonal endings, marked E. In contrast, axonal ending marked EA, in the upper left portion of the section, lacks normal neurosecretory granules and is filled instead with smaller granules. Presumably, EA endings in Brattleboro homozygotes represent the abnormal neurons whose counterparts in normal rats would produce vasopressin. B. Typical electrical recordings, in rats, from an oxytocin‐producing neuron, which has been stimulated by suckling, and from a vasopressin‐producing neuron, which has been stimulated by hemorrhage (HAEM). Both neurons were located in the supraoptic nucleus (SO). The oxytocin cell showed a characteristic burst by firing just prior to releasing oxytocin, as reflected by an increase in intramammary pressure (milk ejection). In contrast, the vasopressin cell showed prolonged, phasic increase in firing rate when 5 ml of blood was removed (HAEM). OT, optic tract. C. Production of vasopressin in a specific neuron of the hypothalamoneurohypophysial system (see text). Oxytocin is produced in an analogous manner in a separate set of cells, except that prooxytocin is not glycosylated. The perikarya of each cell type are found in both the supraoptic and paraventricular nuclei (see Table 1)

From Dyball et al. 38. Modified from Valtin et al. 182. From Morris et al. 109


Figure 5.

A. Normal and mutant genes that encode for the vasopressin precursor (preprovasopressin) in normal rats (Long‐Evans and Wistar strains) and Brattleboro rats, respectively. The arrowheads indicate the deletion of the guanosine nucleotide in the Brattleboro gene and the consequent carboxy terminus of the mutant preprovasopressin (hatched rectangle). CP‐14 is an abnormal 14‐amino acid peptide, which was used for immunocytochemical studies. SP, signal peptide; AVP, arginine vasopressin; NP, neurophysin; GP, glycopeptide; CHO, site of glycosylation. [Slightly modified from Guldenaar et al. 56.] B. Comparisons of mRNAs and the predicted vasopressin precursors in: hypothalamus of normal rats (top); hypothalamus of Brattleboro rats (middle); and adrenal glands and ovaries of Brattleboro rats (bottom). Abbreviations and symbols as given above. Because a stop condon is lacking in the mutant mRNA, its poly (A) sequence is translated in the Brattleboro rat; the resulting polylysine tail is very long in the hypothalamus but relatively short in other organs.

Slightly modified from Ivell et al. 76


Figure 6.

A. Characteristics of normal VII +/+ mice and of four strains of mice with nephrogenic defects of urinary concentration. The open bars indicate urine osmolalities while the mice were eating and drinking at will, and the hatched bars the urine osmolalities after 3 consecutive days of treatment with Pitressin tannate in oil (ADH), 0.25 unit/day given subcutaneously. All values are mean ± SEM; asterisks indicate values that are significantly different from those in VII +/+ animals. b wt, body weight; BUN, blood urea nitrogen. B. Urine osmolalities in DI +/+ Severe and DI +/+ Nonsevere mice eating and drinking at will, plotted as a function of age. The same mice were tested at different ages, although a single mouse was not necessarily examined over the entire time span. Each circle or dot represents the mean of as many as 17 or as few as 2 mice (average, 10 animals). C. Osmolalities of urine (large symbols) and papillary tips (small symbols) in normal VII +/+ mice, and four strains with vasopressin‐resistant defects of urinary concentration. Origin of each line represents the cortical interstitial osmolality; slope of each line, the corticopapillary gradient in that particular strain. Values are means ± SEM.

From Kettyle and Valtin 84. Adapted from Naik and Valtin 112. From Valtin 170


Figure 7.

A. Cascade of events whereby vasopressin is thought to increase water permeability of responsive cells. Reaction involves the V2 receptor for vasopressin. The example given here, which pertains to principal cells of the mammalian collecting duct, is based partly on data obtained in anuran membranes. Uninterrupted arrows denote steps that have been defined; interrupted arrows with question marks, postulated steps. ADH, antidiuretic hormone, or vasopressin; s, stimulatory guanine nucleotide regulatory protein; ATP, adenosine triphosphate; cAMP, cyclic 3′,5′‐adenosine monophosphate; S'AMP, adenosine 5'‐monophosphate; cAMP‐PDE, cyclic AMP phosphodiesterase; IMPs, intramembranous particles. The same cascade initiated through the V2 receptor is thought to be responsible for two other effects of vasopressin, namely, an increase in urea permeability of inner medullary collecting ducts, and an augmentation of NaCl transport in medullary thick ascending limbs of Henle (see Fig. 10A). B, C. Freeze‐fracture replicas of apical (luminal) membranes of principal cells from inner medullary collecting ducts of homozygous Brattleboro rats before (B) and after (C) treatment with vasopressin. In the absence of vasopressin (B), no clusters of intramembranous particles can be seen, whereas in the presence of the hormone (C), there are many such clusters (indicated by arrows). The larger depressions represent microvilli. Shadowing directions are indicated by the arrowheads. Bar = 0.5 μm. D. Relationship between rate of vasopressin infusion in Brattleboro homozygotes and the frequency of intramembranous particle clusters in the apical (luminal) membranes of their collecting ducts. Steep portion of the curve spans physiological range of plasma vasopressin concentration.

From Harmanci et al. 63 From Harmanci et al. 62


Figure 8.

Percentage of collecting duct cells showing clusters of intramembranous particles (IMP) and concurrent urinary osmolalities in normal (VII +/+) mice and in two genotypes with mild (DI +/+ Nonsevere) and marked (DI +/+ Severe) nephrogenic defects of urinary concentration. The cells examined were principal cells from inner medullary collecting ducts. Five of the eight DI +/+ Severe mice were pretreated with large doses of the vasopressin analogue, 1‐desamino‐8‐D‐arginine vasopressin (dDAVP). *, significantly different from VII +/+; †, significantly different from DI +/+ Nonsevere.

From Brown et al. 18


Figure 9.

Aspects of cyclic 3′,5′‐adenosine monophosphate (cAMP) metabolism in collecting ducts of VII +/+ (normal) and DI +/+ Severe mice. Collecting ducts were dissected from the inner stripe of the outer medulla. A. Content of cAMP during basal (B) conditions and after a 20‐min exposure to 10−6 M arginine vasopressin (AVP). Each column and bracket represents the mean ± SEM of 14–15 tubular samples obtained from each of five VII +/+ and five DI +/+ Severe mice. NS, not significant. The difference in basal levels between the two strains was statistically significant, with a P value of < 0.01. B. Activity of cAMP phosphodiesterase (cAMP‐PDE). Columns and brackets represent means ± SEM of five animals in each strain. The difference between the two values was statistically significant, as indicated by a P value of < 0.05. Increased activity of cAMP‐PDE has been demonstrated as well in cortical and inner medullary collecting ducts of DI +/+ Severe mice 49,73. C. Stimulation of adenylate cyclase by a maximal concentration (10−6 M) of arginine vasopressin (AVP). The columns and brackets represent the mean ± SEM of four to six tubular samples obtained from each of four VII +/+ and four DI +/+ Severe animals. While there was not a significant difference in the basal activities (B), the vasopressin‐stimulated activity was significantly lower in DI +/+ Severe than in VII +/+ animals, as indicated by the P value of < 0.005. This difference, however, was no longer apparent when the results were expressed per mm tubule length rather than per unit of protein (see Table III of reference 77), nor was the difference present in inner medullary collecting ducts (Homma et al., unpublished data).

A, B, C from Jackson et al. 77


Figure 10.

A. Locations and actions within the nephron where vasopressin acts to abet the concentration of urine: (1) increased water permeability of the collecting system; (2) increased urea permeability of the final portion of inner medullary collecting ducts; (3) increased reabsorption of NaCl from medullary thick ascending limbs of Henle; and (4) increased glomerular filtration rate in juxtamedullary nephrons. The first three actions are mediated via V2 receptors; the last is probably an indirect effect (see text). md, macula densa. B. Filtration rates in single glomeruli of outer cortical (OC) and juxtamedullary (JM) nephrons in: Brattleboro heterozygous rats (heteros), which have endogenous vasopressin; Brattleboro homozygotes (homos), which lack the hormone; and Brattleboro homozygotes treated with the vasopressin analog l‐desamino‐8‐D‐arginine vasopressin (dDAVP). Symbols represent mean ± SEM. C, D. Aspects of cyclic 3′,5′‐adenosine monophosphate (cAMP) metabolism in medullary thick ascending limbs of Henle of VII +/+ (normal) and DI +/+ Severe mice. The thick ascending limbs were dissected from the inner stripe of the outer medulla. As shown in C, both basal (B) and vasopressin‐stimulated (AVP, 10−6 M) activation of adenylate cyclase were significantly lower in DI +/+ Severe than in VII +/+ animals. There were, however, no significant differences in the activity of cAMP‐phosphodiestcrase (cAMP‐PDE) (D). Each column and bracket represents the mean ± SEM of four to six tubular samples obtained from each of four or five animals. *, significantly lower (P < 0.02) than basal activity (B) in VII +/+ mice; NS, not significant. E. Ratio of the glomerular filtration rate in single juxtamedullary nephrons to the filtration rate in single outer cortical nephrons. In this study, DI +/+ Nonsevere mice served as controls in the sense that, unlike DI +/+ Severe animals, they can render their urine hypertonic to plasma (Fig. 6A) and therefore can respond to vasopressin, at least partially. Bars and brackets denote mean ± SEM; the asterisk reflects a value that is significantly different from DI +/+ Nonsevere mice (P < 0.05). F. Aortic pressure in DI +/+ Severe mice in response to a large intravenous bolus of synthetic aqueous arginine vasopressin (AVP). The heavy line shows the mean response for the five mice. Uosm, urine osmolality.

From Veal and Valtin, unpublished data. Adapted from Valtin 177. Adapted from Trinh et al. 166, and reprinted from Valtin 178. From Jackson et al. 77. Adapted from Trinh et al. 167


Figure 11.

A, B. An experiment in a Brattleboro homozygous rat, which showed that the amount of water reabsorbed from the terminal collecting duct is actually greater during water diuresis (A) than during antidiuresis (B). Each diagram portrays the tip of the papilla in the same rat, before it received vasopressin and after an intravenous infusion of the hormone. Details described in text. The hairpin structure represents a long loop of Henle, and it shows that vasopressin increased the papillary interstitial osmolality from approximately 550 to 925 mOsm/kg H2O. The branched structure is the final ∼ 1 mm of a collecting duct. TF/P osm, ratio of osmolality in tubular fluid to that in plasma; P/TF in, ratio of inulin concentration in plasma to that in tubular fluid. C. Summary of the findings in 18 Brattleboro homozygous rats. Bars and brackets = mean ± SEM.

Slightly modified from Jamison et al. 78


Figure 12.

A. Proportions of the filtered load of water that are reabsorbed in various parts of the nephron during antidiuresis. Unless these approximate amounts are reabsorbed before tubular fluid enters the medullary collecting ducts, the ability to render the urine hyperosmotic to plasma will be curtailed or abolished. B. Inverse correlation, in rats, between the urinary flow immediately before giving vasopressin and the subsequent ability of the kidneys to concentrate urine in response to a very high dose of the hormone (1.0 unit Pitressin tannate in oil, subcutaneously, per rat). Each point represents one animal. For all 45 observations, the correlation coefficient is −0.902. It should be emphasized that this graph is not simply a plot of urinary flow and osmolality in the same sample. Rather, each point represents the flow and osmolality, respectively, during two successive 24 h periods.

From Valtin and Harrington 180


Figure 13.

A. Changes in sodium and water balance in a healthy adult human during sodium chloride depletion (days 1 through 11) and repletion (days 12 through 16). Each vertical arrow denotes a 2 h period that the subject spent in a sweat box. PNa+, plasma sodium concentration. Details described in text. B. Development of hyponatremia during sodium chloride depletion in eight Brattleboro homozygotes, which lack vasopressin, and seven control rats (Brattleboro heterozygotes) that have vasopressin. The serum sodium concentration is known to be higher in Brattleboro homozygotes than in control rats 184; this fact, however, cannot be attributed simply to contraction of the body fluid volumes 50,123. C. Schematic representation of the proposal by Berliner and Davidson 11, whereby the kidneys can retain solute‐free water in the absence of vasopressin. Details given in text.

Adapted from Valtin 174. Adapted from Mc‐Cance 103. Adapted from Harrington 64


Figure 14.

Diagrams summarizing quantitative analysis of the relationship between vasopressin‐producing cell bodies (large dots) in the supraoptic nucleus and their innervation by catecholamine varicosities (small dots). Hypertrophy and increased staining density of the vasopressin‐producing perikarya in the DI Os/ + mice accompanied by a marked increase in the catecholamine varicosities. The four diagrams for each mouse model represent sections at four levels of the supraoptic nucleus, progressing from the rostral (optic chiasm) to the caudal (optic tract) end of the nucleus.

Slightly modified from Davis et al. 32


Figure 15.

A. Preference scores for drinking 2.2% ethanol solution or tap water, and simultaneous total daily fluid intake, in three types of experimental animals: Brattleboro rats; Roman High Avoidance rats (RHA); and mice with nephrogenic defects of urinary concentration. Open columns denote control values; hatched columns, values during high fluid turnover; and crosshatched columns, values during ameliorated fluid turnover. Rationale and interpretation of each experiment are described in the text. Heteros, Homos, Brattleboro heterozygotes and homozygotes, respectively; LVP, lysine vasopressin; RHA +/+, Roman High Avoidance rats lacking the Brattleboro gene; RHA di/di, Roman High Avoidance rats homozygous for the Brattleboro gene; dGAVP, desglycinamide9‐arginine8‐vasopressin; DI + /+ Nonsevere and DI Os/ +, mice with a nephrogenic defect of urinary concentration and with nephrogenic diabetes insipidus, respectively (see Fig. 6). Asterisks denote values that are significantly different from those in animals with high fluid turnover. [Data from Rigter and Crabbe 31,121.] B. Inverse relationship between the total fluid intakes of DI Os/+ mice and their preference scores for drinking 2.2% ethanol solution or tap water. Each point represents one DI Os/+ mouse. The correlation coefficient for this plot is −0.75.

Slightly modified from Crabbe and Rigter 31
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Article Title: Genetic Models of Diabetes Insipidus
 

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Heinz Valtin. Genetic Models of Diabetes Insipidus. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 1281-1316. First published in print 1992. doi: 10.1002/cphy.cp080228