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Divisions of Endocrinology and Metabolism, and Nephrology, Department of Medicine, Georgetown University (Y.T., K.S., T.M., E.A.B., J.G.V.), Washington, D.C. 20007; and the School of Veterinary Medicine, Washington State University (R.C.S.), Pullman, Washington 99164
Address all correspondence and requests for reprints to: Dr. Joseph G. Verbalis, 232 Building D, Georgetown University, 4000 Reservoir Road NW, Washington, D.C. 20007. E-mail: verbalis{at}gunet.georgetown.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vasopressin V2 receptors belong to the seven-transmembrane domain, G protein-coupled receptor superfamily and are mainly present in the renal distal tubules and collecting ducts (5). Activation of vasopressin V2 receptor leads to an increase in intracellular cAMP by stimulating adenylate cyclase activity through Gs. AVP regulates the water permeability of renal collecting tubule cells in two ways. Short term regulation is achieved by shuttling of aquaporin-2 water channels from intracellular vesicles into the apical plasma membrane (6). Long-term regulation occurs through increasing the abundance of aquaporin-2 protein (7) by the action of cAMP response element-binding protein on the cAMP response element in the 5'-flanking region of the aquaporin-2 gene (8). Recent studies from our laboratories have demonstrated that renal vasopressin escape from AVP-induced antidiuresis is accompanied by marked down-regulation of kidney aquaporin-2 protein and messenger RNA (mRNA) expression (9). Additional studies of isolated perfused collecting tubules from animals undergoing escape from antidiuresis have shown a reduced ability to generate cAMP in response to vasopressin stimulation (10). As renal aquaporin-2 protein expression and distribution are mainly regulated by AVP via vasopressin V2 receptor-stimulated adenylate cyclase activation in the kidney, we hypothesized that altered function of inner medullary V2 receptors may contribute to renal vasopressin escape by decreasing cAMP generation and its subsequent effects on aquaporin-2 expression and function. Accordingly, this study was designed to examine whether altered vasopressin V2 receptor binding capacity and/or affinity are associated with the renal vasopressin escape phenomenon in an experimental model of inappropriate antidiuresis in the rat (11).
Because iodination of the tyrosine residue in the pressin ring of AVP interferes with binding to V2 receptors, it has been difficult to perform vasopressin V2 receptor binding studies in kidney inner medulla due to the lack of a suitable radioligand with high specific activity (12, 13). In this report we describe the development of a radioligand binding assay using a novel iodinated V2-selective receptor antagonist with high specific activity to study the vasopressin V2 receptor during renal vasopressin escape. Our results demonstrate that vasopressin V2 receptor binding is markedly decreased during experimental renal vasopressin escape, and that this V2 receptor down-regulation correlates well with the initiation of renal escape from AVP-induced antidiuresis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of kidney inner medullary membranes
Animals were killed by decapitation, and blood samples were
collected for measurement of the plasma sodium concentration. Kidneys
were quickly removed and rinsed with ice-cold buffer A (50
mM Tris-HCl/1.0 mM EDTA solution, freshly added
1.0 µg/ml bacitracin, 0.2 µg/ml aprotinin, and 1.0 µg/ml
leupeptin, pH 7.5) and were then sliced along the corticomedullary axis
to separate the medulla from the cortex. The inner medullary region of
the kidneys was dissected and minced in ice-cold buffer A. The inner
medulla was homogenized with 10 strokes in a glass homogenizer
(Thomas; Swedesboro, NJ) on ice. The resulting homogenate was
centrifuged at 1,000 x g for 10 min at 4 C. The pellet
was discarded, and the supernatant was recentrifuged in ice-cold buffer
A at 15,000 x g for 30 min at 4 C. The membrane
preparations were gently vortexed and resuspended in ice-cold buffer A
to final concentrations of 0.5–1.0 mg protein/ml and were immediately
stored at -80 C. Approximately 0.6–0.7 mg protein can be obtained
from the inner medulla of one rat kidney. Membrane protein
concentrations were determined by protein assay using BSA as the
standard (Bio-Rad Laboratories, Inc., Richmond, CA).
Preparation of vasopressin V2
radioligand
Quantitation of vasopressin V2 receptors
in past studies has been hampered by the lack of ideal radioactive
ligands; iodination of the tyrosine residue in the AVP pressin ring
abolishes ligand binding, and tritiated AVP has low specific activity.
Recently, novel selective V2 receptor antagonists
have been developed that retain surprisingly high
anti-V2 potency by modifying AVP at position 2
(14). In initial experiments, we chose a position 2-modified
V2 antagonist,
d(CH2)5[D-Ile2,Ile4,Tyr-NH29]AVP,
which has been shown to be relatively selective for vasopressin
V2 receptors and has a tyrosine iodination site
at the carboxyl-terminal distant from the ligand-receptor binding site
where an isoleucine has replaced the normal tyrosine residue (courtesy
of Dr. Maurice Manning, Medical College of Ohio, Toledo, OH).
This ligand was iodinated using the chloramine-T method (15), and the
monoiodinated V2 antagonist was purified by
reverse phase (C18) HPLC. Preliminary studies
using this iodinated radioligand ([125I]V2RA)
were performed to determine the optimal conditions for binding to rat
kidney inner medullary membranes.
Vasopressin V2 receptor binding assay
Membrane preparations (20–25 µg protein) were suspended in
300 µl buffer B (buffer A supplemented with 0.1% BSA, pH 7.5) at
0–4 C. For saturation studies, samples were incubated for 50 min at 27
C with concentrations of [125I]V2RA ranging
from 10–800 pM. The binding reaction was terminated by
rapid filtration through Whatman GF/C glass fiber filters
(Clifton, NJ) after the addition of 3 ml ice-cold PBS buffer. Bound
tracer was rapidly separated from unbound tracer by washing filters
four times with ice-cold PBS using a Brandel vacuum harvester (model
M-24, Gaithersburg, MD). Radioactivity was measured in a 
-counter
(Cobra, Packard, Downers Grove, IL). Nonspecific binding was determined
in the presence of 1 µM unlabeled DDAVP.
Preincubation of glass-fiber filters with 10% BSA overnight was used
to reduce nonspecific absorption of the radioligand to the filters.
Specific binding was calculated as the difference between total binding
and nonspecific binding. Vasopressin V2 receptor
binding density (Bmax) and affinity
(Kd) were analyzed by Scatchard analysis using a
nonlinear program of PRISM (GraphPad Software, Inc., San
Diego, CA).
Statistical analysis
All results are expressed as the mean ± SEM,
and differences between groups were analyzed statistically using
one-way ANOVA followed by post-hoc comparisons via the
Student-Newman-Keuls test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The nonspecific
binding component of [125I]V2RA binding
represented approximately 50% of the total binding at 200
pM (a concentration near the Kd) and
40% of the total binding at 50 pM.
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). Incubation of increasing
concentrations of membrane protein ranging from 15–30 µg with 500
pM [125I]V2RA showed that
[125I]V2RA specific binding to kidney inner
medulla membranes was linearly related to the protein concentration
under these conditions (Fig. 2B). Consequently, all further binding
experiments were performed at 27 C using 20–25 µg membrane
protein/sample, and the duration of the binding reaction in the
presence of [125I]V2RA was 50 min unless
otherwise described.
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). Scatchard analysis of the data indicated
a Bmax of 240 ± 12 fmol/mg protein (n
= 8), and an apparent Kd of 0.24 ± 0.04
nM (n = 8) in normal rat kidney inner medullary
membranes (Fig. 3B). This is consistent with reported values from
binding studies, using a similar iodinated agonist performed on rat
vasopressin V2 receptors expressed in COS-7 cells
(16).
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). No significant
differences in V2 receptor binding affinity were
found between untreated and DDAVP-infused rats
(Kd: untreated rats, 0.24 ± 0.04
nM; 5-day DDAVP infusion, 0.36
± 0.05 nM; 6-day DDAVP infusion,
0.34 ± 0.05 nM; 7-day DDAVP
infusion, 0.37 ± 0.06 nM; all
P > 0.05).
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summarizes the physiological data obtained from
DDAVP-control and DDAVP-water loaded rats.
The data show that the plasma sodium concentration significantly
decreased in DDAVP-water loaded rats compared with the
DDAVP-control rats on the first day of water loading,
reflecting a significant degree of water retention induced by the
DDAVP antidiuresis. By the second day of water loading,
urine volume increased, and urinary osmolality decreased significantly
in the DDAVP-water loaded rats compared with the
DDAVP-control rats despite ongoing DDAVP
infusions, indicating the onset of renal escape from the
DDAVP-induced antidiuresis.
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summarizes the vasopressin
V2 receptor binding densities and affinities from
the two experimental groups of rats on each day of the water loading.
The data show that by day 1 of water loading, no difference in
vasopressin V2 receptor binding was found between
the DDAVP-control rats and the DDAVP-water
loaded rats (n = 8; P > 0.05), but by the second
day of water loading, vasopressin V2 receptor
binding fell to 77% of that in DDAVP-control rats (n
= 12, P < 0.05), and by the third day of water
loading, vasopressin V2 receptor binding
decreased to 43% of that in DDAVP-control rats (n =
10, P < 0.01). These results indicate that water
loading can further down-regulate the vasopressin
V2 receptor and also suggest that
DDAVP-independent factors probably play a significant role
in renal escape with prolonged water loading. No significant difference
in vasopressin V2 receptor affinity
(Kd) was observed between
DDAVP-control rats and DDAVP-water loaded
rats (P > 0.05).
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compares the time courses of urine
water excretion changes and down-regulation of vasopressin
V2 receptor expression. Figure 5A shows that
urine volume significantly increased by the second day of the water
loading, which indicates the onset of the escape response. Figure 5B
shows that the down-regulation of vasopressin V2
receptor expression also started by the second day of water loading.
These results indicate that the down-regulation of vasopressin
V2 receptors correlates temporally with the onset
of renal vasopressin escape.
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compares the vasopressin
V2 receptor binding among the normal untreated
rats, the DDAVP-control rats, and the
DDAVP-water loaded rats (after 3 days of water loading).
From these data, it is clear that the elevated DDAVP in
plasma significantly reduced vasopressin V2
receptor binding, and that water loading induced a further significant
down-regulation of vasopressin V2 receptor
binding.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To perform these studies, we first developed an assay using a novel iodinated V2 selective receptor antagonist (20) with high specific activity to perform vasopressin V2 receptor binding measurements in rat kidney inner medulla. As iodination of the tyrosine residue in the pressin ring of AVP abolishes binding to the vasopressin V2 receptor in the kidney, tritiated vasopressin with low specific activity has been the only radioligand available for renal vasopressin V2 receptor binding studies for many years. The low specific activity binding efficiency of the tritiated vasopressin has hampered vasopressin V2 receptor studies, especially when limited sample sources from small animal models have to be used. For example, at least 100–300 µg membrane protein/sample is necessary for binding analysis when using tritiated AVP in the rat kidney medulla (21, 22). Therefore, to obtain sufficient kidney medulla membranes for one saturation Scatchard analysis, kidneys from at least three to five animals have to be pooled. Recently, some 125I- and 35S-labeled vasopressin analogs have been developed for receptor binding studies; however, the majority of these ligands are either V1 receptor selective, or they have high binding affinities to both V1 and V2 receptors (12, 13, 20). Another limitation is that some of these iodinated ligands (e.g. N-[125I]L-Tyr-[Lys8]vasopressin) are very unstable and degrade to such an extent during the incubation period that no specific binding is detectable at 37 C (13).
In the present study we developed a binding assay for the high specific activity V2 selective antagonist [125I]V2RA to quantitate vasopressin V2 receptor function. Under the assay conditions employed, only 20–25 µg membrane protein/sample was needed for vasopressin V2 receptor analysis. Thus, only one or two rats are required per saturation curve using [125I]V2RA compared with three to five rats using a tritiated ligand. Under these assay conditions, the binding of [125I]V2RA to rat kidney inner medulla membranes was shown to be rapid, saturable, dependent on the membrane protein concentration, and less than 10% of the total radiolabeled ligand concentration was bound. Thus, radioligand binding assay conditions were developed that meet the criteria necessary for determination of Bmax and Kd Scatchard analysis. Saturation curves from 10–800 pM [125I]V2RA revealed a single population of high affinity V2 receptors in rat inner medullas. These results indicate that the [125I]V2RA ligand is a useful tool for analyzing vasopressin V2 receptor expression in the rat kidney.
Our studies show that vasopressin V2 receptor binding expression in kidney inner medulla is down-regulated during renal escape from DDAVP-induced antidiuresis. Previous work reported that alterations of renal concentrating ability are associated with down-regulation of vasopressin V2 receptors under some physiological and pathophysiological circumstances (17, 18). For example, rats in chronic renal failure exhibit a marked decrease in vasopressin V2 receptor density and the virtual absence of V2 receptor mRNA without changes in other G protein-coupled receptors. Based on these findings, it has been proposed that vasopressin resistance in chronic renal failure is due at least in part to a selective down-regulation of vasopressin V2 receptors as a consequence of decreased V2 receptor mRNA expression (18). Another example is dehydration. When AVP levels in plasma are elevated by 72 h of water deprivation, the vasopressin V2 receptor density (Bmax) in renal tubular epithelial basolateral cells is reduced by 38% without affecting the affinity (Kd) of the receptor (17). This phenomenon seems somewhat paradoxical, as vasopressin V2 receptor density was reduced in animals that needed more water conservation. One potential explanation for this phenomenon is that the kidney may possess spare V2 receptors (17, 23, 24, 25), such that larger decreases in receptor density are required before second messenger levels (in this case cAMP) are affected. Decreases in vasopressin V2 receptor density also have been observed in aged rats. However, the data regarding the likely cause of vasopressin V2 receptor down-regulation with aging are contradictory (21, 22). Some investigators have found that aging is accompanied by a tendency toward a reduction in plasma AVP levels; however, other investigators did not find a significant difference in vasopressin levels between young and old rats (22). These opposing observations can be explained by the different experimental models employed, but also suggest the possibility that the down-regulation of vasopressin V2 receptors may occur via more than one mechanism.
The present study indicates that elevated DDAVP in plasma is partially responsible for the down-regulation of the V2 receptor in the kidney inner medulla during the escape process. After 5 days of DDAVP infusion, vasopressin V2 receptor binding was decreased to 72% of that in normal untreated rats. Prolongation of the DDAVP infusion from 5 to 7 days did not induce further decreases in vasopressin V2 receptor binding, suggesting that the down-regulation induced by elevated DDAVP occurred over a limited time period and did not progress after prolonged DDAVP exposure. The vasopressin V2 receptor is a member of the seven-transmembrane domain, G protein-coupled receptor superfamily. Although agonist-induced receptor down-regulation has been reported in a number of G protein-coupled receptors (26), the mechanisms of agonist-induced receptor down-regulation have not been well studied for vasopressin V2 receptors. Ligand-induced internalization of the V2 and V1a receptors via coated pits was demonstrated in pig tubular epithelial cells and rat smooth muscle cells, respectively (27, 28). As observed for other G protein-coupled receptors, receptor internalization only occurred in response to agonist, but not antagonist, binding. These findings suggest that internalization depends on receptor activation of intracellular signaling pathways.
The lateral mobility of agonist-receptor complexes in the plasma membrane lipid bilayer is also an important determinant in G protein-coupled receptor signaling (e.g. activation of adenylate cyclase) (29). After incubation of medullary tubules with AVP for 4 h, 82% of specific bound receptor was internalized by the cells (30). After removing the AVP, most (90 ± 6%) of the internalized receptor recycled back to the surface. This agonist-induced vasopressin V2 receptor internalization and recycling are not dependent on receptor protein resynthesis (30). In our experiments, rats were continuously infused with DDAVP for 5–7 days. This extended period of DDAVP stimulation may have caused increased receptor internalization and abnormal recycling of the vasopressin V2 receptor. An alternative explanation is that elevated plasma DDAVP induced a decrease in V2 receptor mRNA expression. Firsov reported that in vivo administration of DDAVP induced a selective down-regulation of V2 receptor mRNA expression by 50% but without changing V1a receptor mRNA expression (31).
The present study also indicates that DDAVP-independent
mechanisms associated with water loading are involved in
down-regulation of vasopressin V2 receptor
function. Our animal model enabled us to compare the time course of
changes in urine volume and in vasopressin V2
receptor binding to determine whether the regulation of
V2 receptor binding coincided with the onset of
the escape as indicated by increases in urine volume. Figure 5
shows
that the time course of vasopressin V2 receptor
down-regulation coincides with the initiation of the renal escape from
DDAVP-induced antidiuresis. Perhaps the most significant
finding of this study is that DDAVP-independent mechanisms
may be more responsible for the renal vasopressin escape phenomenon.
The differences in vasopressin V2 receptor
binding between the DDAVP-control rats and
DDAVP-water loaded rats represents the down-regulation of
vasopressin V2 receptor expression induced by
DDAVP-independent factors. As shown in Table 2,
vasopressin V2 receptor binding in
DDAVP-water loaded rats fell to 77% of that in
DDAVP-control rats (n = 12; P <
0.05) by day 2 of water loading, and by the third day of water loading,
vasopressin V2 receptor binding decreased further
to 43% of the DDAVP-control level (n = 10;
P < 0.01). This finding therefore suggests that
DDAVP-independent factors are important in renal
vasopressin escape with the continued water loading. These findings are
also consistent with recent studies demonstrating that vasopressin
V2 receptors can be regulated by AVP-independent
factors. Lithium significantly decreased V2
receptor binding in rat renal papillary collecting duct membranes
without significantly altering plasma AVP levels (32), consistent with
earlier studies showing that lithium down-regulated AVP-stimulated cAMP
generation in cultured rat inner medullary collecting tubule cells
(33). Similarly, oral administration of chlorpropamide increased the
density of AVP V2 receptors in rat renal papilla
tissue without changing plasma AVP levels (34).
If down-regulation of V2 receptor binding is in part responsible for renal escape from antidiuresis by decreasing cAMP levels in medullary collecting duct cells, thereby decreasing both the synthesis and the membrane insertion of aquaporin-2 water channels, then it might be asked why the DDAVP down-regulation of receptor binding itself does not cause a similar process. Two explanations are possible to explain the lack of this observed effect. First, the collecting tubule cells may possess spare receptors (17, 23, 24, 25), as discussed previously, such that larger decreases in receptor binding are necessary to impact upon coupled adenylate cyclase activity and cAMP levels. Second, the antidiuresis caused by DDAVP may indeed be submaximal as a result of the induced down-regulation of receptor function, but this would not be seen as an escape from the DDAVP-induced antidiuresis if it occurred very rapidly. Both these and other possibilities will require further study using in vitro expression of V2 receptors
Finally, if down-regulation of vasopressin V2 receptor binding is indeed causally related to the observed escape from vasopressin-induced antidiuresis, then it would be appropriate to consider potential mechanisms underlying this down-regulation. One obvious possibility is that local changes in plasma or tissue osmolality might be sufficient to cause mechanical perturbations of the basolateral membranes of collecting duct cells, which could, in turn, affect receptor dimerization or receptor internalization and recycling, as discussed previously for the agonist-stimulated down-regulation. However, recent studies have not supported an important role for either plasma or tissue osmolality in the escape process (35). Alternatively, the decreased receptor binding might reflect a true decrease in receptor number mediated either by down-regulated receptor synthesis or up-regulated receptor degradation. Recent studies of kidney AVP V2 mRNA expression have supported the former possibility (36). In this case further studies will be necessary to identify the signal(s) responsible for down-regulation of AVP V2 receptor synthesis. These will probably include humoral and/or hemodynamic factors that reflect expansion of the extracellular fluid volume, as this is well known to be critical for the production of escape from antidiuresis (1, 2, 3, 4).
In summary, we have used a new radioligand to quantitate vasopressin V2 receptor binding in the kidney. Using these methods, we have confirmed that elevated AVP in plasma causes vasopressin V2 receptor down-regulation in the kidney, but also that DDAVP-independent mechanisms related to water loading cause further vasopressin V2 receptor down-regulation during escape from vasopressin-induced antidiuresis. Thus, we have demonstrated for the first time that vasopressin V2 receptors in the rat kidney inner medulla are markedly down-regulated during escape from vasopressin-induced antidiuresis. Although these findings do not prove that the measured changes in V2 binding are causally related to renal escape from the effects of vasopressin, the strong temporal correlation between the receptor down-regulation and the initiation of physiological renal escape is consistent with this hypothesis. It is tempting to speculate that similar changes in receptor binding and transporter function might underlie other physiological escape processes as well, such as escape from excess mineralocorticoids, but this possibility must await future studies of receptor binding and expression and/or transporter expression specific to each situation.
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Acknowledgments |
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Footnotes |
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Received July 15, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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