Nephrol Dial Transplant (1996) 11: 622-627
Nephrology
Dialysis
Transplantation
Original Article
Lithium induced polyuria and renal vasopressin receptor density
Johannes Hensen, Monika Haenelt and Peter Gross
Department of Medicine, Divisions of Endocrinology and Nephrology, Universitats-Klinikum Steglitz, Freie Universitat
Berlin, and Med. Klinik I, Friedrich-Alexander-Universitat Erlangen-Nuremberg, Germany
Abstract
Background. Lithium, a drug frequently used for treatment of affective disorders, is known to cause a vasopressin resistant state, leading to polyuria and
polydipsia. It has been suggested that lithium interacts
with the renal V2-vasopressin receptor. Detailed studies
on the influence of lithium on the AVP receptor,
however, have so far been difficult due to the lack of
a suitable radioligand with high specific activity and
high affinity.
Methods. Using 125I-[8-(p-(OH)-phenylpropionyl)]LVP, we studied the effects of lithium on V2-vasopressin receptors in male Sprague-Dawley rats and LLCPKj cells. Rats, having free access to water, were orally
treated with 10 mg lithium/100 mg b.w./day or placebo
for 10 days. Scatchard analysis was performed using
membranes prepared from homogenized renal papillae.
Results. Lithium caused significant polyuria and an
impaired renal concentration capacity after water
deprivation. Binding studies showed no effect of
lithium on binding affinity KD (0.98 + 0.21 nmol/1 vs.
0.86 + 0.15 nmol/1 (Li) (n.s.). Receptor density, however, significantly decreased from 130 + 12.3 nmol/kg
protein in controls (« = 8) to 101.7+ 13.4 nmol/kg protein (n = 8), (P<0.05). Plasma osmolality and AVP
were not significantly altered by lithium treatment.
Vasopressin receptor density on LLC-PK^-cells, a pig
renal cell line, was not changed by preincubation with
lithium (312 ±22 nmol/kg vs. 329 + 25 nmol/kg (Li)
(w = 6, n.s.).
Conclusions. The decrease of AVP-receptor density in
vivo might be related to vasopressin resistance, either
primary, or secondary to other factors, e.g. actual
water transport.
AVP-receptors [1-3]. In the complete absence of vasopressin, the clinical syndrome of diabetes insipidus
develops, characterized by a maximally diluted urine
and an inability to conserve water [4,5]. Defects in the
primary structure of vasopressin receptors lead to the
syndrome of congenital nephrogenic diabetes insipidus
[6]. Much more frequently, however, is the acquired
form of ADH resistance [5]. By virtue of its widespread
use in the treatment of affective disorders, lithium has
emerged as perhaps the most common cause of
acquired nephrogenic diabetes insipidus [7,8]. The
mechanism by which lithium opposes the antidiuretic
effect of AVP is not clear, however [9]. Recently,
Marples et al. [10] have demonstrated an effect of
lithium in the collecting duct of the rat to decrease the
density of apical water channels (aquaporin-2), possibly explaining at least some of the lithium-induced
nephrogenic diabetes insipidus [10]. This however,
does not exclude a role of vasopressin receptors. A
direct effect of lithium on the renal V2-receptor has
only recently addressed by binding studies [11]. These
studies, however, have been hampered by the lack of
a radioligand with high specific activity and high
affinity for the renal V2-AVP-receptor. We have
recently developed such a radioligand and proven its
usefulness in examination of small amounts of biological material [12-14]. In the present study, we examined the effect of oral lithium administration on V2AVP-receptors of plasma membranes from rat renal
papillary collecting ducts ex vitro. In addition, to
control for any possible direct effects of lithium on the
vasopressin receptor, we tested the effects of lithium
on AVP receptors of LLC-PKj cells, a renal cell line
known for its high vasopressin receptor density.
Key words: lithium; vasopressin; polyuria; vasopressin
receptor; vasopressin resistance
Methods
Introduction
Experimental animals
Sprague-Dawley rats were obtained from Versuchstieranstalt
Hannover, Germany. Research animals were acquired and
used in compliance with federal and Berlin laws and instituCorrespondence and offprint requests to: Johannes Hensen, M.D., tional regulations.
Forty-eight male Sprague-Dawley rats (b.w. 250-300 g)
Department of Medicine I, Division of Endocrinology and
were kept in metabolic cages. Food and water were provided
Metabolism. Krankenhausstr. 12. 91054 Erlangen. Germany.
It is well established that vasopressin (AVP) acts on
the collecting tubule through cAMP-generating V2-
C 1996 European Dialysis and Transplant Association-European Renal Association
623
Lithium therapy and vasopressin resistance
ad libitum. One group of 24 animals was treated orally for Preparation of radioligand l25I-8(pf0HJ10 days with 10 mg of lithium/100 g b.w. daily (given as 1% phenylpropionyl) -L VP
lithium carbonate solution twice daily by gastric tube) for a
period of 10 days, 24 controls received the same volume in 125I-8(p[OH]-phenylpropionyl)-LVP, a ligand with high
the form of vehicle fluid. The lithium dose used in these affinity to V,- and V,-AVP-receptors comparable to AVP,
experiments has been shown in earlier experiments to lead was prepared and used as described previously [12]. In brief,
to lithium concentrations of 0.44 + 0.03 mmol/1 in plasma prior to conjugation, the free a-amino group of LVP
[9,15]. This dose has also not been shown to lead to (Bachem) was blocked by incubation in 68% acetone for
morphological changes, as judged by light or electron micro- 48 h. 10 ng acetone-LVP was then reacted with 1 mCi
scopy [9,15]. After decapitation at day 10, blood was col- of [125I]-[8-(p(OH)-phenylpropionyl-N-hydoxysuccinimidyl
lected in ammonium-heparinized tubes for measurements of ester in 20 ul N,./v~-dimethylformamide (DMF) and triethylAVP plasma concentration and of plasma osmolality. amine (TEA) (1:100 v/v). Conjugation was allowed to
Kidneys were rapidly removed and papillae were prepared proceed for 4 h at room temperature. The conjugated label,
as described before.
diluted in 150 ul of 0.1% trifluoroacetic acid (TFA), was
A water deprivation test was performed in 15 male then purified by C-18 reverse-phase high pressure liquid
Sprague-Dawley rats (8 lithium treated rats, 7 placebo- chromatography (HPLC). The isopropylidene moiety protreated rats). After 10 days of treatment with lithium or tecting the a-amino group was removed by heating the
placebo, a water deprivation test was performed for 36 h. peptide for 30 min in 1 ml 0.2 M acetic acid in a boiling
Urine volume and urine osmolality were measured every 12 h. water bath before the second HPLC purification. The fractions with AVP-like immunoreactivity in the second HPLC
run were stored at 4°C in 2 ml ethanol-water-acetic acid
(80:20:4). Due to the large difference in the retention times
Materials
between the a-amino protected and deprotected peptide
Unless stated otherwise, chemicals were from Merck, specific activity of the iodinated tracer approached the theorDarmstadt, and Sigma, Heidelberg (Germany). (3-[125l]- etically maximal value (~2000 Ci/mmol). In the presence of
iodotyrosyl2)-vasopressin-[Arg8]
and
[125l]-[8-(p(OH)- bacitracin, binding of the radioligands to a membrane prephenylpropionyl-N-hydoxysuccinimidyl ester were from paration of LLC-PK, cells or rat renal papillary membranes
was rapid, saturable, and reversible [17].
Amersham, Braunschweig, Germany.
Preparation of plasma membranes of rat renal papillae
Binding studies
Kidneys were removed and the renal papilla was placed in
Tris buffer at 4°C (100 mM Tris-Cl, 0.5 mM EDTA, 1 g/1
bacitracin, pH 7.8, 21°C). Tissue was homogenized with a
mechanical Ultra Turrax® (Jahnke & Kunkel, Staufen,
Germany) and a potter homogenisator at highest speed of
rotation. The homogenate was centrifuged for 5 min at lOOg
(4°C). Supernatant was again centrifuged for 20 min in a
Sorvall® centrifuge at 3000 g (4°C). The pellet was resuspended in a binding Tris-HCl buffer (100 mM Tris-Cl,
5mM MgCl2, pH 7.8, 21°C).
Renal papillary membranes. For one binding study the papillae of 3 rats were pooled. Binding experiments were carried
out as cold saturation studies, as described previously [12].
We have demonstrated previously that 125I-[8-(p-(OH)phenylpropionyl)]-LVP and AVP have identical affinities for
the AVP-V2-receptor in saturation studies [12]. Increasing
amounts of unlabeled arginine vasopressin (0 to
510~ 8 mol/l) and a constant concentration of radiolabeled
vasopressin (60000 cpm/tube) were used. This tracer concentration corresponds to 20 fmol per tube at a specific activity
of 2000 Ci/mmol and a counting efficiency of 78%.
Nonspecific binding was assessed in the presence of excess
AVP (10~6-10"~5 M). Incubation was performed for 90 min
at room temperature in a binding buffer with the following
components: 100 mM Tris-Cl, 5 mM MgCl2, 0.1% BSA,
0.1% bacitracin, pH 7.8. The incubation assay (150 |il) contained 50 ul papillary membrane homogenisate (containing
at least 20 |ig of papillary membrane protein per tube), 50 ul
standard and 50 ul radioligand. Incubation was terminated
by adding 750 ul iced buffer (lOOmM Tris-Cl, 10 mM
MgCl2, pH7.8, 21°C). After centrifugation at 39000g
(14 min, 4°C) the supernatant was removed and the procedure was repeated. The pellet was counted for 10 min in a
gamma scintillation counter (Packard).
LLC-PKi plasma cell membranes. Binding experiments with
membranes of LLC-PK,-cells (>20ug protein/tube) were
carried out as described previously [12]. In brief, increasing
amounts of unlabeled LVP (0 to 5-10~8 mol/1) and a constant
concentration of radiolabeled VP (60000 cpm/tube) were
used. Nonspecific binding was assessed in the presence of
excess LVP (10" 6 -10~ 5 M). The binding assay conditions
were otherwise identical to the method described above.
Vasopressin radioimmunoassay. Radioimmunoassay of vasopressin was performed by a method described by Morton
el al. [18], as described previously [19]. In brief, heparinized
Cell culture and membrane preparation
LLC-PK, cells (ATCC CRL 1392, 181. passage) were grown
and cultured as described previously [14]. In order to study
the effect of preincubation with lithium, cells were grown for
the last 2 days before harvesting with and without 2 mmol/1
lithium chloride. Cells were then detached from the culture
dish by incubation for 15 min with 0.1% sodium EDTA,
0.15 M NaCl and 50 mM Tris-Cl, pH 7.4. Plasma cell membranes from LLC-PK, cells were prepared by resuspension
in hypotonic Tris-Cl buffer (5 mM, pH 7.4) containing 3 mM
MgCl2, and 1 mM Na2EDTA, followed by homogenization
using 10 strokes in a tightly fitting Potter-Elvehjam homogenizer and two subsequent centrifugations in a high speed
Eppendorf microcentrifuge after resuspending in hypotonic
Tris buffer.
Protein determination
Protein concentration was determined using the Bio-Rad*
protein kit with IgG as standard [16]. Colour reaction was
measured at 578 nm in an Eppendorf photometer.
624
J. Hensen et al.
blood samples were centrifugated for 20 min at 3000 r.p.m.
(4°C). AVP was extracted from plasma using CIS-reversephase-cartridges (Sep-pak®, Water Associates, Milford,
Mass. USA). After elution with methanol extracts were dried
and dissolved in 150 ul buffer (0.005 M Tris-HCl, pH 7.5,
0.525% human serum albumin, 0.35% neomycin sulfate).
AVP-standard was from the WHO Institute London
(320pg/ml). The assay contained 50 ul AVP-extract or
-standard, 50 ul antibody and 50 ul tracer (0.5 pg/50 ul).
Incubation period was 72 h at 4°C. The incubation was
terminated by addition of 1 ml of 1% iced dextran-coatedcharcoal-suspension followed by centrifugation at 1600 g for
10 min. The supernatant containing bound AVP was counted
for 20 min in a gamma scintillation counter. Plotting of the
standard curve and calculation of the results were accomplished with the help of a computer program (spline function).
Plasma osmolality was measured by freezing point depression
using an automatic digital osmometer (Roebling
MeCtechnik, Berlin).
Statistics. Scatchard plots were computed by 'Ligand' [20].
Results were statistically analysed with Mann-Whitney U
test. Data are given as mean + SEM.
Table 2. Results of a water deprivation test in 8 rats treated with
lithium for 10 days and 7 controls
Urinary volume
[ml/12 h]
Urine osmolality
[mosmol/kg]
Time (h)
Lithium
Controls
12
24
36
12
24
36
82.0 + 5.6*
15.1+2.7*
5.3 + 0.5*
313 + 26.8*
658 + 83.3*
1415 + 127*
18.0+1.4
4.2 + 0.4
3.1+0.5
1041+65.8
1249 + 87
1817 + 7 '
*/><0.05 compared to controls.
As high AVP-levels could not be related to an elevated
plasma osmolality in these rats, stress induced AVPsecretion was regarded as the most probable cause of
the high AVP-concentration in these animals.
The results of the water deprivation test is given in
Table 2. After water deprivation for 36 h maximal
urine osmolality in Li rats was significantly lower than
in the control group (1415 + 127 mosmol/kg vs.
1817 + 6 mosm/kg, /*<0.05). Urinary volume during
Results
the last 12 h of water deprivation was significantly
higher after Li (5.3 + 0.5 ml versus 3.1 +0.5 ml,
Mean baseline 24-h urinary volume in 24 lithium P<0.05).
treated rats (Li rats) and 24 control rats was 10.7 + 0.6
Binding of 125I-8(p[OH]-phenylpropionyl)-LVP to
12.4
+
0.9
ml,
respectively.
Baseline
water
intake
and
papillary ADH-receptors of rat papillary membranes
was 22.6+1.8 ml and 24.6 + 2.0 ml, respectively. Water was specific and saturable, as reported previously [21].
intake and urinary volume significantly increased Mean total bound and nonspecific binding averaged
during treatment with lithium (Table 1), reaching a 9% of total counts, and 35% of total bound, respect24-h urinary volume of 43.2+ 3.2 ml on day 10 of ively. Treatment with lithium significantly decreased
lithium treatment in that group of animals.
density of AVP-receptors (Table 3). Receptor density
In six out of 48 rats, determination of plasma (#MAX) was 101.7+ 13.4 nmol/kg protein in the lithium
osmolality and AVP was not possible because insufficient material was obtained for determination. Plasma Table 3. Individual KD and BMAX of vasopressin receptors of rat
osmolality
10 days
after
treatment
was renal papillary membranes after oral administration of lithium or
304.7 + 3.14mosm/kginLirats(«=15)and303.0±2.3 placebo for 10 days
mosm/kg in controls (« = 21) (n.s.) (Table 2). Plasma
AVP after treatment with lithium (1.47 + 0.35; « = 15) Experiment no.
MAX
D
[nmol/kg]
tended to be higher than in the control group
[nmol/1]
(1.25 + 0.31; n = 2l; n.s.) (Table 1). Inclusion of four
lithium-treated rats and two control rats with extremely Lithium
113
0.91
high AVP-levels ( » 2 SD higher than mean) also did 1
94
0.67
2
not lead to significant differences between both groups. 3
98
0.63
Table 1. Water intake, urinary volume, plasma AVP and plasma
osmolality after 10 days of treatment with lithium (n = 24) or placebo
(n = 24)
Lithium group
Water intake [ml/day]
Urinary volume
[ml/day]
Pl-AVP [ng/1]
Pl-OSM [mosmol/kg]
57.0 + 3.0*
43.2±3.2*
1.47 + 0.35 («=15) +
304.7±3.1 (n=15)
4
5
6
7
8
0.47
1.75
0.44
1.19
0.82
103
178
81
41
106
mean + SEM
0.86 ±0.15
101.7 + 13.4*
Controls
1
2
3
4
5
6
7
8
0.60
0.51
0.42
0.58
2.04
0.66
1.67
1.33
203
105
121
141
154
109
110
98
mean + SEM
0.98 ±0.21
130.1 ±12.3
Control group
28.2+1.1
15.6±1.2
1.25+0.31 (« = 21)
303.0±2.3(n = 21)
*/><0.05 compared to controls. Insufficient blood for determination
of AVP was collected in six rats. + Three lithium rats with excessive
AVP levels (>90 ng/1) and one lithium rat with an AVP concentration of 19.1 ng/1 were not included in the calculation. Also, two
control rats (>90 ng/1 and 16.9 ng/1) were excluded.
* Significant (P<0.0S) versus control group.
625
Lithium therapy and vasopressin resistance
Table 4. Individual KD and BMAX of vasopressin receptors of LLCPK,-cells after preincubation with or without lithium for 2 days (n.s.)
Experiment no.
[nmol/kg]
[nmol/1]
Lithium
1
2
3
4
5
6
0.47
0.46
0.46
0.90
0.42
0.51
388
361
241
397
290
301
mean + SEM
0.54 + 0.1
329 ±25
Control
1
2
3
4
5
6
0.50
0.68
0.66
0.72
0.44
0.49
386
225
300
343
310
305
mean + SEM
0.58 ±0.1
312±22
#MAX
group (« = 8) and 130.1 ±12.3 nmol/kg protein in the
controls (« = 8) (P<0.05). Binding affinity (A:D) was
not significantly different (0.86 ±0.1 nmol/1 after
lithium vs. 0.98 + 0.21 nmol/1 in the control group).
Receptor
density
on LLC-PK^-cells was
312 + 22 nmol/kg
protein
without
lithium.
Preincubation with Li did not change receptor density
significantly (329 + 25 nmol/kg protein, n = 6, n.s.). KD
was 0.58 ±0.1 nmol/1 and 0.54 + 0.1 nmol/1, respectively (n.s.).
Discussion
The present results confirm the findings by numerous
authors (for review see [8,22-24] that lithium induces
polyuria, polydipsia and an impairment in renal concentration capacity.
The mechanism that leads to polyuria after lithium
is not clear. Animal studies have demonstrated an
effect of lithium to stimulate thirst very early in the
course of lithium administration [25], but this
dipsogenic effect is not evident after more prolonged
administration [26]. In some reported patients polyuria
was also—in part—attributable to lithium induced
polydipsia [27].
The suggestion that lithium impairs vasopressin
secretion from the pituitary [28] is not supported by
thefindingof several authors [26,29,30]. Lithium probably causes reciprocal changes in the secretion and
action of vasopressin by diminishing the renal sensitivity to AVP, while increasing the sensitivity of the
vasopressin secretory response to osmotic stimulation
[27,29]. In our study, plasma vasopressin and plasma
osmolality were not significantly increased after
lithium. There was a tendency towards a higher plasma
osmolality and plasma vasopressin after lithium, however, the relation between vasopressin and lithium in
the present study was not significantly changed. In
summary, our data do not confirm an altered relationship between vasopressin and plasma osmolality after
lithium.
With respect to the kidney, convincing evidence has
been presented in the literature showing a lithium
induced nephrogenic diabetes insipidus [31,32]. This is
also in accordance with the findings of the present
study. Thus, when lithium rats in our study were
subjected to a water deprivation test, maximal urinary
concentration was found to be impaired. Under these
circumstances any possible lithium induced thirst was
without importance, because of the water deprivation.
In addition, our measurements demonstrated comparable plasma AVP-levels in lithium treated rats and
controls after 10 days of treatment. We have not
measured plasma AVP at the end of the water deprivation; however, it is known that plasma AVP is increased
under these conditions [29]. Thus, it is very likely that
the impairment of maximal urinary concentration
occurred in the presence of ample vasopressin, which
is characteristic of nephrogenic diabetes insipidus.
Urinary concentration is primarily dependent on at
least submaximal stimulation of renal collecting duct
principal cell vasopressin receptors and subsequent
maximal 'insertion' of aquaporin-2 water channels into
the luminal cell membrane. In a recent study in the
rat, using antibodies to aquaporin-2, Marples et al.
[10] were able to demonstrate that lithium induced a
dramatic reduction by approximately 66%, in the density of collecting duct apical aquaporin-2 channels.
Although this study did not attempt to directly test
the consequences of such a reduction on hydraulic
permeability of the collecting duct, it is now highly
likely that some of the lithium-induced nephrogenic
diabetes insipidus will be accounted for by the reduction in water channels that can be inserted in response
to AVP in the presence of lithium.
It has been suspected previously that lithium impairs
cellular cAMP generation after stimulation by the
appropriate hormone. In fact this is suggested to be
the mechanism of lithium induced hypothyroidism
[33]. Whether a similar mechanism applies to the
kidney—and how it might come about—has not clearly
been established. Detailed studies could demonstrate
that lithium decreases vasopressin, but not cAMPstimulated water flow in the toad bladder, thus suggesting a defect in vasopressin induced cAMP generation [34]. Several studies have subsequently been able
to confirm the defect in the vasopressin receptor adenylate cyclase cascade [35,36]. In this respect, the present
study sought to determine whether AVP receptor density might be involved. This has been difficult to study
in the past, because the available vasopressin analogues
for studying renal V2-AVP receptors either have a low
affinity and high specific activity or vice versa [11].
This was overcome in our study by using a recently
developed radioligand with high affinity and high
specific activity [12]. We observed that renal papillary
vasopressin receptor density was significantly reduced
after lithium treatment. The renal papilla contains
626
primarily collecting duct cells, although it also contains
interstitial cells, vasa rectae (capillary) tissue, and thin
ascending and descending limbs of Henle. It is well
known that the majority of renal papillary vasopressin
receptors are V2-vasopressin-receptors from collecting
ducts, and only few Vrvasopressin receptors are present. Taken together our study suggests that V2-vasopressin receptors are reduced on basolateral
membranes of renal papillary collecting duct cells.
Similar changes might occur on cortical collecting
tubules as well. Although we did not measure cAMP
generation in such tissue it is possible that it might be
reduced to a comparable extent as was the density of
AVP receptors and that this then might contribute to
the lithium induced nephrogenic diabetes insipidus.
The opposite, i.e. an concomitant increase in AVP
receptor density and cAMP production was recently
demonstrated after chlorpropamide treatment [21].
An imbalance between V r and V2-vasopressin receptors might, however, also be of some importance. For
instance, prostaglandins, stimulated by the V,-vasopressin-receptor action of AVP, are well known to
reduce the V2-induced production of cAMP in collecting duct cells and thus their AVP-dependent
increase in water permeability [37,38]. Rather than
just a diminishment in the number of AVP receptors,
an imbalance between both receptor subtypes could
also be involved in the lithium induced concentrating
defect. It would thus be interesting to study the binding
of both V r and V2-vasopressin receptor ligands in the
same membrane preparation.
The mechanism (s) behind these changes remain to
be determined. For instance, it is conceivable that
lithium causes interstitial changes in the papilla which
are then associated with alterations of receptor density.
This may be tested in future studies. However, our
present experiments suggest that a direct influence of
lithium per se on the vasopressin receptor might be
unlikely, since our observations on LLC-PKrcells are
negative. Indeed, this negative finding in LLC-PK r
cells is not in accordance with the working hypothesis.
A possible explanation for this divergence is that LLCPKpcells are derived from pig proximal tubule cells
and possess a somehow different vasopressin receptor
[39]. Unfortunately there are basically no other renal
cell lines showing a high density of vasopressin receptors than LLC-PKj-cells. A promising model to study
might be V2-AVP-receptors of isolated renal collecting
tubules. Another explanation for our divergence is that
the conditions of urinary concentration themselves are
necessary to bring about the receptor changes observed
under lithium. For example, the reduction in apical to
basolateral water-flow, induced by a severely reduced
density of apical water channels as discussed recently
[10] might be related to a correspondingly reduced V2vasopressin receptor-density. In other words on the
basis of published works by others [10] in conjunction
with the present observation, collecting duct principal
cells might be subject to 'cross-talk' or a negative
feedback between apical and basolateral events, with
respect to water transport. Since it appears possible to
J. Hensen et al.
manipulate aquaporin-2 water channels by techniques
of molecular biology, and since related changes may
not only induce nephrogenic diabetes insipidus but
also the opposite—i.e. hyponatremia—this hypothesis
appears to be one which should be tested in studies in
the near future.
Acknowledgements. The technical assistance of P. Exner and
U. Dieckmann is greatly acknowledged. We thank Dr Jacques
A. Durr for helpful suggestions and discussions, and Dr J. J. Morton
for kindly providing the vasopressin antibody. This work was
supported in part by the Deutsche Forschungsgemeinshaft (He
1472/6-2).
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Received for publication: 28.9.95
Accepted in revised form: 8.1.96