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1 Division of Endocrinology, Georgetown University, Washington, District of Columbia 20007; 2 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Sodium transport is increased
by vasopressin in the cortical collecting ducts of rats and
rabbits. Here we investigate, by quantitative immunoblotting, the
effects of vasopressin on abundances of the epithelial sodium channel
(ENaC) subunits (
, 
, and 
) in rat kidney. Seven-day infusion
of 1-deamino-[8-D-arginine]-vasopressin (dDAVP) to
Brattleboro rats markedly increased whole kidney abundances of - and
-ENaC (to 238% and 288% of vehicle, respectively), whereas
-ENaC was more modestly, yet significantly, increased (to
142% of vehicle). Similarly, 7-day water restriction in Sprague-Dawley rats resulted in significantly increased abundances of - and -
but no significant change in -ENaC. Acute administration of dDAVP (2 nmol) to Brattleboro rats resulted in modest, but significant, increases in abundance for all ENaC subunits, within 1 h. In
conclusion, all three subunits of ENaC are upregulated by vasopressin
with temporal and regional differences. These changes are too slow to
play a major role in the short-term action of vasopressin to stimulate
sodium reabsorption in the collecting duct. Long-term increases in ENaC
abundance should add to the short-term regulatory mechanisms (undefined
in this study) to enhance sodium transport in the renal collecting duct.
immunoblotting; sodium transporters; collecting duct; Brattleboro rat; aldosterone
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE POSTERIOR-PITUITARY HORMONE, vasopressin, has been shown to increase both sodium (9, 18, 20, 40, 41, 47, 51) and water reabsorption (19, 33) in the kidney collecting duct of rats and/or rabbits. Its role in water reabsorption has been well described. Briefly, vasopressin, acting through the vasopressin V2 receptor, can increase water permeability of the collecting duct both by acutely regulating trafficking of aquaporin-2 (22, 35) and, over a longer time frame, by increasing transcription and thus influencing the total number of aquaporin-2 (10, 23, 36, 49) and aquaporin-3 (13, 14, 49) water channel molecules in the principal cells of the collecting duct.
The role of vasopressin in the regulation of sodium balance is not as clear. Several investigators have shown, in acute studies, that in vitro application of vasopressin will increase sodium transport in perfused cortical collecting ducts (CCD) from rat (9, 20, 40, 41, 45, 51) or rabbit, (9, 18) as well as in primary rabbit CCD suspensions (7) and in several cell lines such as A6 cells (cultured toad kidney cells) (3, 52) and M-1 cells (derived from mouse CCD) (34). Furthermore, in perfused tubules the effect was additive to, and thus independent from, the increase in transport observed with aldosterone (9, 2, 41). Furthermore, in several of the above perfused-tubule studies, it was shown that without pretreatment of animals with mineralocorticoids, sodium transport in response to vasopressin was nearly imperceptible in the CCDs (41, 51). Less work has been done examining the chronic effects of vasopressin on sodium transport in the kidney. Djelidi et al. (11) have reported that chronic exposure to vasopressin will increase 22Na influx in RCCD1 (rat CCD) cells. However, the effects of chronically elevated vasopressin levels, in vivo, on sodium transport capacity in this segment have not been studied.
Sodium transport across the apical membrane of the cortical and outer
medullary collecting duct occurs primarily through the amiloride-sensitive epithelial sodium channel (ENaC) (2 ).
This channel, in the kidney, is a hetero-multimer made up of three distinct, yet homologous subunits: , and . Cloning of the three subunits from rat colon (6, 8) has made
it possible to study the molecular regulation of these proteins. We, as
well as others (11, 12, 42),
have made antibodies against each of the subunits. Our antibodies are
peptide-derived, polyclonal antibodies directed against a region in the
carboxy tail of - and -ENaC and against a region in the amino
tail of -ENaC (28). These antibodies are unique in that
they are sufficiently sensitive to detect ENaC in native tissues by immunoblotting.
Vasopressin V2 receptor mRNA has been localized, by both in
situ hybridization (38) and RT-PCR (19,
25, 48), to the same tubule segments that
express ENaC, that is, the connecting tubule and the collecting duct.
The V2 receptor is coupled to adenylyl cyclase through
Gs activation in these cells. The long- and short-term
antidiuretic actions of vasopressin are found to be primarily mediated
by increased cellular cAMP levels. Chronic exposure to vasopressin is
thought to lead to increased expression of aquaporin-2 protein via
potentially multiple effects on regulatory motifs (or elements) in the
5'-flanking region of the gene. One such element is the CRE (cAMP
regulatory element), which increases transcription rates for this
protein (29). Interestingly, a CRE has also been found in
the 5'-flanking region of -ENaC (50). Moreover, Djelidi
et al. (11) have shown vasopressin-stimulated increases in
transcription and translation of both - and -ENaC in
RCCD1 cells. Thus the purpose of these studies was to
evaluate the effects of both acute and chronic elevation of circulating levels of vasopressin [or the V2-specific receptor
agonist, 1-deamino-(8-D-arginine)-vasopressin (dDAVP)] on
-, -, and -ENaC subunit abundances in the rat kidney by
quantitative immunoblotting.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and Study Design
For these experiments, four different groups of animals were studied. In the first, 12 male Brattleboro rats (250 g), under light methoxyflurane (Metofane, Schering-Plough Animal Health, Union, NJ) anesthesia, were implanted with osmotic mini-pumps (Alzet model 2001; Alza, Palo Alto, CA) to administer 20 ng/h dDAVP, the V2-receptor-selective agonist of vasopressin (n = 6) or saline vehicle (n = 6) for 7-days. In the second study, 205-g male Sprague-Dawley rats were water restricted for 7 days by offering a limited amount of water as a part of a slurry diet (23). "Restricted" rats (n = 6) were given 15 ml water · 200 g body wt
1 · day1 mixed with 15 g of
powdered food. Control rats (n = 6) were given 37 ml
water · 200 g body wt1 · day1
mixed with 15 g of powdered food. Rats in both groups consumed all
of their diet daily and maintained weight throughout the 7-day period.
In the third study, 12 male Brattleboro rats (250 g) were given a
single acute intramuscular injection of 2 nmol of dDAVP dissolved in
saline (n = 6) or saline alone (vehicle)
(n = 6) and euthanized after 1 h. The fourth study
was the same as the third study, but the rats were euthanized after
only 30 min. In all studies, rats were euthanized by decapitation, and
both kidneys were rapidly removed and either frozen on dry ice for
later processing or immediately dissected and homogenized in a buffered
isolation solution as described below.
Western Blotting
Preparation of samples. Immediately after euthanasia (or after thawing), kidneys were placed in chilled-buffered isolation solution containing 250 mM sucrose, 10 mM triethanolamine (Calbiochem, La Jolla, CA), 1 µg/ml leupeptin (Bachem, Torrance, CA), and 0.1 mg/ml phenylmethylsulfonyl fluoride (US Biochemical, Toledo, OH) adjusted to pH 7.6. Whole right kidneys were homogenized using a tissue homogenizer (Omni 2000; Omni International, Warrenton, VA) fitted with a 10-mm micro-sawtooth generator in 10 ml isolation solution on ice. The left kidney was dissected into cortex and inner stripe of the outer medulla. Each region was separately homogenized in either 10 ml (cortex) or 1 ml (outer medulla) of isolation buffer while on ice.
Protein concentrations of the homogenates were measured by the Pierce BCA Protein Assay Reagent Kit (Pierce, Rockford, IL). All samples were then diluted with isolation solution to a protein concentration of between 1 and 3 µg/µl and solubilized at 60°C for 15 min in Laemmli sample buffer. Samples were stored at
80°C until ready to
run on gels.
Electrophoresis and blotting of membranes. Initially, "loading gels" were done on each sample set. Five micrograms of protein from each sample was loaded into an individual lane, and electrophoresed on 12% polyacrylamide gels (precast; Bio-Rad, Hercules, CA), and then stained with Coomassie blue dye (G-250, Bio-Rad; 0.04% solution made in 3.5% perchloric acid). Gels were then destained with water, and selected bands were scanned (Scan Jet 6100C; Hewlett-Packard, Palo Alto, CA) to determine density (NIH-Image software) and relative amounts of protein loaded in each lane. Finally, protein concentrations were "corrected" to reflect these measurements.
For immunoblotting, 10-30 µg of protein from each sample were loaded into individual lanes of precast minigels of 7, 10, or 12% polyacrylamide (Bio-Rad). The proteins were transferred from the gels electrophoretically to pure nitrocellulose membranes (Bio-Rad). After a 30-min, 5% milk block, membranes were probed overnight at 4°C with the desired affinity-purified polyclonal antibody. The production, purification, and characterization of the- (L766), - (L558), and
- (L550) ENaC antibodies has been previously described in detail
(28). Our anti-aquaporin-2 antibody (L414) was made to the
same peptide as our previously used L127 antibody (10,
13, 35, 36, 49) and
gives a similar labeling pattern. Likewise, our anti-NHE3 antibody
(L546) (18) and our anti-NCC antibody (L573)
(24) have been previously characterized. For probing
blots, all antibodies were diluted into a solution containing 150 mM
NaCl, 50 mM sodium phosphate, 10 mg/dl sodium azide, 50 mg/dl Tween 20, and 0.1 g/dl bovine serum albumin (pH 7.5). The secondary antibody was
goat anti-rabbit IgG conjugated to horseradish peroxidase (Kirkegaard
and Perry Laboratories, Gaithersburg, MD) used at a concentration of
0.1 µg/ml. Sites of antibody-antigen reaction were visualized using
luminol-based enhanced chemiluminescence (LumiGLO; Kirkegaard and Perry
Laboratories) before exposure to X-ray film (Fujifilm; Fugi Medical
Supplies, Stamford, CT).
Statistics
Relative intensities of the resulting immunoblot band densities were determined by laser scanning (Scanjet 6100C) followed by analysis with NIH IMAGE software. The statistical significance of the effects of the various treatments on expression was determined by an unpaired t-test of densitometry values when standard deviations were equivalent, or by Welch's t-test when standard deviations were significantly different (Prism software; Graphpad, San Diego, CA). P < 0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic dDAVP Infusion or Water Restriction Increases Aquaporin-2 Abundance
As a positive control, aquaporin-2 protein levels were examined in the whole kidney homogenates in the Brattleboro rats from the chronic dDAVP infusion study and from the water restriction study (Sprague-Dawley rats) (see METHODS). Previous studies (10, 36, 49) have shown an increase in this collecting duct protein with elevated vasopressin levels. In Fig. 1A, an immunoblot is shown in which whole kidney homogenates from Brattleboro rats given an infusion for 7 days of either vehicle (n = 6) or dDAVP (20 ng/h) (n = 6) were probed with our anti-aquaporin-2 (L414) antibody. Each lane was loaded with a sample from a different rat. Preliminary Coomassie-stained gels were examined to assess equivalency of loading. Densitometry of the nonglycosylated form of aquaporin-2 (the 29-kDa band) and the glycosylated form of aquaporin-2 (the bands that fall between ~36 and 47 kDa) was performed, and the values were summed. As we predicted, band density for aquaporin-2 was significantly increased (to 463% of the vehicle level) in the dDAVP-infused rats. Furthermore, water restriction of Sprague-Dawley rats also significantly increased band density for aquaporin-2 to 201% of the level observed in their control (water-replete) animals (Fig. 1B).
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Chronic dDAVP Infusion Increases -, -, and -ENaC
Abundance
- (L766), anti-- (L558) or
anti--ENaC (L550) antibodies, respectively. In response to dDAVP
infusion, - and -ENaC were substantially increased (Fig. 2,
B-D), whereas -ENaC showed a more moderate, yet
still significant, increase (Fig. 2, A and D).
Average band density of -ENaC in the dDAVP-infused rats was
increased to 142% of the vehicle mean, whereas the average band
densities for - and -ENaC were increased to 238% and 288% of
the vehicle mean, respectively (Fig. 2D).
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Water Restriction Increases - and -ENaC Abundance
1 · day1; "control") or "water restricted" (15 ml
water · 200 g body wt1 · day1) for a total of 7 days. Figure 3D shows
densitometric quantification of the immunoblots. As above, each lane
was loaded with a sample from a different rat. In response to water
restriction, a similar pattern of expression was observed as seen with
dDAVP infusion, although the increases in - and -ENaC were
smaller. In Fig. 3A, the immunoblot was probed with
polyclonal anti--ENaC antibody (L766). Although -ENaC tended to
be increased, band density was not significantly affected by water
restriction. Average band density of -ENaC in the water-restricted
rats was 122 ± 12% of the control mean (P = 0.18). Figure 3B shows an immunoblot loaded with whole
kidney homogenates and probed with polyclonal anti--ENaC antibody
(L558). Similar to the dDAVP infusion, -ENaC abundance was
significantly increased by water restriction. Band density was
increased to 189 ± 14% of the control mean (P = 0.002) (Fig. 3D). In Fig. 3C, a similarly loaded
immunoblot was probed with polyclonal anti--ENaC antibody. The band
density for the major band associated with -ENaC was likewise
increased by water restriction [band density was 143 ± 13% of
the control mean, P = 0.028 (Fig. 3D)].
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Chronic dDAVP Infusion, but not Water Restriction, Increases the Abundance of the Thiazide-Sensitive NaCl Cotransporter
We also assessed the effects of chronically elevated vasopressin levels on two additional sodium transporters: NCC, the thiazide-sensitive, apically located NaCl cotransporter found in the distal convoluted tubule; and NHE3, the sodium/hydrogen exchanger (type III) found in proximal tubules and the thick ascending limb. Figure 4A shows an immunoblot of whole kidney homogenates from the dDAVP-infused Brattleboro rats and their vehicle controls probed with our anti-NCC antibody (L573) (24). NCC abundance was increased significantly (band density was 241% of vehicle mean) by the dDAVP infusion. Figure 4B shows an immunoblot of whole kidney homogenates from control (water-replete) Sprague-Dawley rats and water-restricted rats. With this treatment, there was no change in NCC abundance (mean band density for water-restricted group = 93% of control mean). Figure 4, C and D, shows similar blots that were probed with our anti-NHE3 antibody (L546) (16). NHE3 abundance was not affected in either study.
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Acute Exposure to dDAVP Results in Increased Abundance of Cortical ENaC Subunits
In studies designed to examine acute (30-60 min) effects of vasopressin on ENaC abundance, modest, yet significant, increases in ENaC subunit abundances were observed. However, this rapid response was only observed in the cortex homogenates. Figure 5 shows a bar graph summarizing the changes in-, -, and -ENaC expression in the cortex (Fig.
5A) and the outer medulla (Fig. 5B) of the
dDAVP-treated Brattleboro rats after 30 or 60 min of exposure to dDAVP
(values have been normalized to their vehicle controls = 100%).
In the cortex, both - and -ENaC abundances were significantly
increased after 30 min, and - and -ENaC abundances were increased
after 60 min (Fig. 5A). In contrast, in the outer medulla no
significant effects of dDAVP were observed in this short time frame
(Fig. 5B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Vasopressin has been shown by several investigators
(9, 18, 20, 40,
41, 45, 51) to acutely increase
sodium transport in the CCD of rats and/or rabbits. This transport has been shown to be amiloride sensitive in many of these experiments, suggesting enhanced transport through the apically located
amiloride-sensitive ENaC, which is the principal port of sodium entry
into these cells (2). With recent cloning of the three
subunits of ENaC, , , and , from the rat colon
(7, 9), we are now able to study potential
molecular mechanisms responsible for ENaC regulation. Nevertheless, it
is important to note that in contrast to the above acute studies, the
regulation of sodium transport in the collecting duct by chronically
elevated blood vasopressin levels has not yet been adequately studied.
It may well be that, like many other proteins, e.g., aquaporin-2,
chronic and acute regulation are accomplished by different mechanisms
(10, 22, 35, 36). In these studies, we examined the effects of elevated blood vasopressin levels on ENaC subunit abundance after both chronic (7-day infusion of
dDAVP, or water restriction) or acute (single injection of dDAVP)
exposure. Our principal finding was that all three ENaC subunits, ,
, and , are increased by vasopressin, with the increases in and being most pronounced. We show increased whole kidney abundance
of -, -, and -ENaC after a 7-day infusion of dDAVP to
Brattleboro rats and an increase in whole kidney and abundance
after 7-day water restriction to Sprague-Dawley rats. Furthermore, in
Brattleboro rats exposed acutely to dDAVP, increased abundances of
cortical - and -ENaC at 30 min and cortical - and -ENaC at
60 min were apparent. In contrast, the abundances of ENaC subunits in
the outer medullary collecting duct were more resistant to change in
response to dDAVP exposure; no changes were apparent in the acute
studies, and only -ENaC was increased after chronic dDAVP.
Chronic Vasopressin Increases -, -, and -ENaC Abundance In
Vivo
and transcription rates and ENaC activity in the
rat cortical collecting duct cell line, RCCD1. In the
studies of Djelidi et al. (11) in vitro incubation of the
cells with vasopressin resulted in a rapid and sustained (up to 10 h) increase in amiloride-sensitive short-circuit current and
22Na transport. The RNase protection assay showed a rapid
(within 1-3 h) increase in -ENaC mRNA, with no change in
-ENaC mRNA. Furthermore, in situ hybridization showed an increase in
-ENaC mRNA within 24 h. Treatment with actinomycin D blocked
these changes in mRNA, suggesting that increased transcription was
responsible for the changes in and rather than decreased
degradation of the mRNA. These studies also showed an increase in the
rate of protein synthesis of both - and -ENaC, but not
-ENaC, as assessed by immunoprecipitation of 35S-labeled
proteins. When transcription was blocked by actinomycin D, the
vasopressin-induced increase in short-circuit current was no longer
apparent, suggesting a potentially important role for changes in ENaC
subunit abundance to regulate sodium transport capacity of the cells.
Our results are similar in that - and -ENaC expression is
increased, but somewhat in contrast with the above studies, we observed
an increase in -ENaC abundance after 30 min and 7 days of dDAVP
infusion. These differences could be a result of -ENaC being
increased by a mechanism other than transcriptional or translational regulation in our studies. For example, the rate of degradation of
-ENaC protein might be retarded with high circulating vasopressin levels. Alternatively, it is possible that chronic administration of
dDAVP to Brattleboro rats corrected the relative aldosterone deficiency
that is normally apparent in untreated Brattleboro rats
(4, 31, 32). Although
Brattleboro rats have normal or elevated plasma renin activity and
angiotensin II (ANG II) levels, their aldosterone levels are
approximately twofold lower than their parent strain, the Long-Evans
rat (4, 31, 32). The defect in
the Brattleboro rat has been proposed to be due to several possible
mechanisms. First, these rats may have a decreased secretion of
adrenocorticotropic hormone (ACTH) from the pituitary (5).
In vitro studies have shown that dDAVP is also a potent V1B
vasopressin receptor agonist (43), and Sakai et al.
(44) revealed that dDAVP directly stimulates ACTH release
from corticotropic adenoma cells through V1B vasopressin
receptors. Second, the defect could be at the level of the adrenal,
i.e., depressed adrenal responsiveness as result of decreased ANG II
(46) or ACTH receptors on the adrenal gland or
post-receptor-mediated events (4, 27). Thus
the increase in -ENaC expression after chronic dDAVP might, in part,
result from increased circulating aldosterone, as it has been reported
by several investigators that -ENaC mRNA (1, 15, 37) or protein abundance
(28) is markedly increased by increases in circulating
aldosterone levels. In support of this mechanism, we also found that
expression of whole kidney NCC, the NaCl cotransporter of the distal
convoluted tubule, was significantly increased by the dDAVP infusion,
relative to vehicle infusion (Fig. 4) even though the distal convoluted
tubule is believed to lack V2 receptors. NCC abundance has
recently been reported (24) to be increased by high
circulating levels of aldosterone in Sprague-Dawley rats either infused
with aldosterone or fed a low-salt diet. Finally, we observed that,
like -ENaC, NCC abundance was not upregulated by water restriction.
Therefore, it is possible that -ENaC and NCC may have been increased
with chronic dDAVP infusion due to a vasopressin-mediated restoration of normal circulating aldosterone levels. Nevertheless, increased aldosterone levels would not likely explain our observation of increased cortical -ENaC abundance after only 30-min exposure to
dDAVP. Furthermore, it is possible that NCC abundance is regulated differently in response to elevated vasopressin in Brattleboro rats
(the strain in which the dDAVP-infusion studies were performed) than it
is in Sprague-Dawley rats (the strain in which the water restriction
studies were performed). Additional studies will need to be done to
sort out specific mechanisms.
Is -ENaC Abundance Rate Limiting for Sodium Transport?
-ENaC appears to be the only
subunit of the three that has been reported to be transcriptionally
regulated by aldosterone (1, 15,
37, 47), a hormone which clearly upregulates
sodium reabsorption in the collecting duct. May et al.
(30) have postulated that -ENaC abundance is rate
limiting for assembly of the multimeric ENaC complex; thus sodium
transport might be expected to be proportional to -ENaC abundance.
Therefore, increased - and -ENaC abundance (as we have observed
here) with little concurrent change in -ENaC abundance might be
predicted to have little impact on net NaCl absorption. However, the
physiological benefit of having increased - and -ENaC expression
might become significant, in so far as NaCl reabsorption is concerned,
if -ENaC is upregulated and no longer rate limiting, for instance,
by high aldosterone levels. This might occur, for example, during
volume depletion, when vasopressin and aldosterone would be predicted
to work synergistically to increase NaCl reabsorption. Further studies
will be required to assess the impact of differential regulation and
subunit stoichiometry on sodium transport.
Potential Role in Acute Upregulation of Sodium Transport
The rapid time frame in which increases in abundance of ENaC subunits occur (30-60 min) would suggest that these abundance changes might be an important component of the acute stimulation of sodium transport in perfused CCDs when vasopressin is added to the bath. Reif et al. (40, 41), Tomita et al. (51), Frindt and Burg (18), and others have observed increased sodium transport that occurs within 20 min, in perfused tubules from rats and/or rabbits. The fact that vasopressin increases- and -ENaC abundance (and possibly also -ENaC) in
the 30-min time frame, might partly explain why vasopressin's action
to increase sodium transport appears to be additive to that of
mineralocorticoids (20, 41), as their
mechanisms for activating ENaC may be distinct. However, the relative
magnitude of the increase in transport observed when vasopressin is
applied to the bath in perfused tubule studies (about 3- to 4-fold)
would suggest that mechanisms in addition to increased subunit
abundance most likely are responsible for increased sodium absorption
in the CCD. For instance, trafficking or phosphorylation of any of the
ENaC subunits may be an important component of regulation of ENaC
activity. Protein kinase A has been reported to increase patch-clamp
current in A6 cells (39), and Kleyman et al.
(26) have evidence suggesting that ENaC is redistributed
to the apical plasma membrane with arginine vasopressin stimulation in A6 cells.
Cortical Collecting Duct Appears Most Sensitive to Vasopressin
Another interesting finding from our acute studies was that the vasopressin-mediated changes in ENaC abundance were mainly, and almost exclusively, observed in the cortical homogenates (CCD) compared with the outer medullary homogenates (outer medullary collecting duct). The reason for this striking difference is unclear. The interstitial environment of the medulla is quite different from that in the cortex, particularly with regard to the increase in osmolality. Furthermore, different paracrine factors may be present, such as prostaglandins. Additionally, although vasopressin V2 receptors have clearly been localized to all regions of the collecting duct (17, 25, 38, 48), the number of active binding sites or post-receptor intracellular signaling may be different along the length of the collecting duct.In conclusion, we find a marked increase in whole kidney abundances of
- and -ENaC with chronic exposure to vasopressin in rats.
Furthermore, -ENaC abundance is also increased, but much more
modestly, and only after dDAVP infusion. Increased subunit abundances
might be expected to result in increased amiloride-sensitive sodium
transport capacity of the collecting duct. In addition, we find rapid
(within 30-60 min) increases in abundances of all three subunits
in response to vasopressin. These changes could be predicted to play
some role in the increased transport of sodium observed in perfused
CCDs when vasopressin is added to the bath, although additional
mechanisms are likely to be involved. These combined results therefore
suggest that vasopressin is involved in both salt and water
conservation, through regulation of ENaC abundance, during
water-deprived states, or during states of acutely elevated blood
vasopressin, such as hemorrhage.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-38094 and K01-DK-02672-01 to Georgetown University (to C. A. Ecelbarger and J. G. Verbalis) and by the intramural budget of the National Heart, Lung, and Blood Institute (to C. A. Ecelbarger, G-H. Kim, J. Terris, S. Masilamani, C. Mitchell, I. Reyes, and M. A. Knepper).
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. A. Ecelbarger, Bldg D, Rm 232, Georgetown Univ., 4000 Reservoir Rd NW, Washington, DC 20007 (E-mail: ecelbarc{at}gunet.georgetown.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 2 November 1999; accepted in final form 8 February 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 H. Amlal, S. Sheriff, and M. Soleimani Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1019 - C1030. [Abstract] [Full Text] [PDF]
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S. W. Kim, W. Wang, J. Nielsen, J. Praetorius, T.-H. Kwon, M. A. Knepper, J. Frokiaer, and S. Nielsen Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats Am J Physiol Renal Physiol, May 1, 2004; 286(5): F922 - F935. [Abstract] [Full Text] [PDF]
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B. W. M. van Balkom, J. D. Hoffert, C.-L. Chou, and M. A. Knepper Proteomic analysis of long-term vasopressin action in the inner medullary collecting duct of the Brattleboro rat Am J Physiol Renal Physiol, February 1, 2004; 286(2): F216 - F224. [Abstract] [Full Text] [PDF]
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 B. C. Willis, K.-J. Kim, X. Li, J. Liebler, E. D. Crandall, and Z. Borok Modulation of ion conductance and active transport by TGF-{beta}1 in alveolar epithelial cell monolayers Am J Physiol Lung Cell Mol Physiol, December 1, 2003; 285(6): L1192 - L1200. [Abstract] [Full Text] [PDF]
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J. Song, M. A. Knepper, J. G. Verbalis, and C. A. Ecelbarger Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1125 - F1137. [Abstract] [Full Text]
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J. Nielsen, T.-H. Kwon, J. Praetorius, Y.-H. Kim, J. Frokiaer, M. A. Knepper, and S. Nielsen Segment-specific ENaC downregulation in kidney of rats with lithium-induced NDI Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1198 - F1209. [Abstract] [Full Text]
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O. A. Weisz and J. P. Johnson Noncoordinate regulation of ENaC: paradigm lost? Am J Physiol Renal Physiol, November 1, 2003; 285(5): F833 - F842. [Abstract] [Full Text] [PDF]
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M. Auberson, N. Hoffmann-Pochon, A. Vandewalle, S. Kellenberger, and L. Schild Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin Am J Physiol Renal Physiol, September 1, 2003; 285(3): F459 - F471. [Abstract] [Full Text] [PDF]
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J. Lebowitz, B. An, R. S. Edinger, M. L. Zeidel, and J. P. Johnson Effect of altered Na+ entry on expression of apical and basolateral transport proteins in A6 epithelia Am J Physiol Renal Physiol, September 1, 2003; 285(3): F524 - F531. [Abstract] [Full Text] [PDF]
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 K. T. Beutler, S. Masilamani, S. Turban, J. Nielsen, H. L. Brooks, S. Ageloff, R. A. Fenton, R. K. Packer, and M. A. Knepper Long-Term Regulation of ENaC Expression in Kidney by Angiotensin II Hypertension, May 1, 2003; 41(5): 1143 - 1150. [Abstract] [Full Text] [PDF]
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J. Loffing and B. Kaissling Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human Am J Physiol Renal Physiol, April 1, 2003; 284(4): F628 - F643. [Abstract] [Full Text] [PDF]
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O. A. Itani, K. L. Cornish, K. Z. Liu, and C. P. Thomas Cycloheximide increases glucocorticoid-stimulated alpha -ENaC mRNA in collecting duct cells by p38 MAPK-dependent pathway Am J Physiol Renal Physiol, April 1, 2003; 284(4): F778 - F787. [Abstract] [Full Text] [PDF]
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K. Y. Na, Y. K. Oh, J. S. Han, K. W. Joo, J. S. Lee, J.-H. Earm, M. A. Knepper, and G.-H. Kim Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats Am J Physiol Renal Physiol, January 1, 2003; 284(1): F133 - F143. [Abstract] [Full Text] [PDF]
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H. L. Brooks, S. Ageloff, T.-H. Kwon, W. Brandt, J. M. Terris, A. Seth, L. Michea, S. Nielsen, R. Fenton, and M. A. Knepper cDNA array identification of genes regulated in rat renal medulla in response to vasopressin infusion Am J Physiol Renal Physiol, January 1, 2003; 284(1): F218 - F228. [Abstract] [Full Text] [PDF]
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S. Masilamani, X. Wang, G.-H. Kim, H. Brooks, J. Nielsen, S. Nielsen, K. Nakamura, J. B. Stokes, and M. A. Knepper Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction Am J Physiol Renal Physiol, October 1, 2002; 283(4): F648 - F657. [Abstract] [Full Text] [PDF]
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P.-Y. Martin, M. Bianchi, F. Roger, L. Niksic, and E. Feraille Arginine vasopressin modulates expression of neuronal NOS in rat renal medulla Am J Physiol Renal Physiol, September 1, 2002; 283(3): F559 - F568. [Abstract] [Full Text] [PDF]
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J. A. Schafer Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct Am J Physiol Renal Physiol, August 1, 2002; 283(2): F221 - F235. [Abstract] [Full Text] [PDF]
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M. A. Knepper Proteomics and the Kidney J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1398 - 1408. [Abstract] [Full Text] [PDF]
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H. L. Biner, M.-P. Arpin-Bott, J. Loffing, X. Wang, M. Knepper, S. C. Hebert, and B. Kaissling Human Cortical Distal Nephron: Distribution of Electrolyte and Water Transport Pathways J. Am. Soc. Nephrol., April 1, 2002; 13(4): 836 - 847. [Abstract] [Full Text] [PDF]
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C. Nicco, M. Wittner, A. DiStefano, S. Jounier, L. Bankir, and N. Bouby Chronic Exposure to Vasopressin Upregulates ENaC and Sodium Transport in the Rat Renal Collecting Duct and Lung Hypertension, November 1, 2001; 38(5): 1143 - 1149. [Abstract] [Full Text] [PDF]
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C. A. Bickel, J. G. Verbalis, M. A. Knepper, and C. A. Ecelbarger Increased renal Na-K-ATPase, NCC, and beta -ENaC abundance in obese Zucker rats Am J Physiol Renal Physiol, October 1, 2001; 281(4): F639 - F648. [Abstract] [Full Text] [PDF]
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L. Dijkink, A. Hartog, C. H. Van Os, and R. J. M. Bindels Modulation of aldosterone-induced stimulation of ENaC synthesis by changing the rate of apical Na+ entry Am J Physiol Renal Physiol, October 1, 2001; 281(4): F687 - F692. [Abstract] [Full Text] [PDF]
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D. Rotin, V. Kanelis, and L. Schild Trafficking and cell surface stability of ENaC Am J Physiol Renal Physiol, September 1, 2001; 281(3): F391 - F399. [Abstract] [Full Text] [PDF]
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 T. Inoue, H. Nonoguchi, and K. Tomita Physiological effects of vasopressin and atrial natriuretic peptide in the collecting duct Cardiovasc Res, August 15, 2001; 51(3): 470 - 480. [Abstract] [Full Text] [PDF]
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H. Hager, T.-H. Kwon, A. K. Vinnikova, S. Masilamani, H. L. Brooks, J. Frokiaer, M. A. Knepper, and S. Nielsen Immunocytochemical and immunoelectron microscopic localization of {alpha}-, {beta}-, and {gamma}-ENaC in rat kidney Am J Physiol Renal Physiol, June 1, 2001; 280(6): F1093 - F1106. [Abstract] [Full Text] [PDF]
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 M. Robert-Nicoud, M. Flahaut, J.-M. Elalouf, M. Nicod, M. Salinas, M. Bens, A. Doucet, P. Wincker, F. Artiguenave, J.-D. Horisberger, et al. Transcriptome of a mouse kidney cortical collecting duct cell line: Effects of aldosterone and vasopressin PNAS, February 15, 2001; (2001) 51603198. [Abstract] [Full Text]
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G.-H. Kim, S. W. Martin, P. Fernandez-Llama, S. Masilamani, R. K. Packer, and M. A. Knepper Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake Am J Physiol Renal Physiol, September 1, 2000; 279(3): F459 - F467. [Abstract] [Full Text] [PDF]
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M. Robert-Nicoud, M. Flahaut, J.-M. Elalouf, M. Nicod, M. Salinas, M. Bens, A. Doucet, P. Wincker, F. Artiguenave, J.-D. Horisberger, et al. Transcriptome of a mouse kidney cortical collecting duct cell line: Effects of aldosterone and vasopressin PNAS, February 27, 2001; 98(5): 2712 - 2716. [Abstract] [Full Text] [PDF]
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