Department of Cell Physiology, University Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands
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ABSTRACT |
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Primary
cultures of immunodissected rabbit connecting tubule and cortical
collecting duct cells were used to investigate the effect of apical
Na+ entry rate on aldosterone-induced transepithelial
Na+ transport, which was measured as benzamil-sensitive
short-circuit current (Isc). Stimulation of the
apical Na+ entry, by long-term short-circuiting of the
monolayers, suppressed the aldosterone-stimulated benzamil-sensitive
Isc from 320 ± 49 to 117 ± 14%,
whereas in the presence of benzamil this inhibitory effect was not
observed (335 ± 74%). Immunoprecipitation of
[35S]methionine-labeled -rabbit epithelial
Na+ channel (rbENaC) revealed that the effects of
modulation of apical Na+ entry on transepithelial
Na+ transport are exactly mirrored by
-rbENaC protein
levels, because short-circuiting the monolayers decreased
aldosterone-induced
-rbENaC protein synthesis from 310 ± 51 to
56 ± 17%. Exposure to benzamil doubled the
-rbENaC protein
level to 281 ± 68% in control cells but had no significant
effect on aldosterone-stimulated
-rbENaC levels (282 ± 68%).
In conclusion, stimulation of apical Na+ entry suppresses
the aldosterone-induced increase in transepithelial Na+
transport. This negative-feedback inhibition is reflected in a decrease
in
-rbENaC synthesis or in an increase in
-rbENaC degradation.
rabbit kidney; cortical collecting duct; connecting tubule; epithelial sodium channel; benzamil
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INTRODUCTION |
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THE MINERALOCORTICOID
HORMONE aldosterone plays a major role in Na+
homeostasis and, consequently, in extracellular volume regulation by
controlling epithelial Na+ channel (ENaC) expression in the
kidney (14). The ENaC complex, consisting of three
subunits, -,
-, and
-ENaC, is present in the apical membrane
of epithelial cells in the distal kidney, distal colon, salivary
glands, sweat glands, respiratory tract, and taste buds (3,
23). It has been demonstrated that upregulation of ENaC
expression by aldosterone differs among mammals (23) and
is also tissue specific (30, 32).
There are three possible mechanisms for aldosterone to enhance
Na+ transport: first, the synthesis and insertion of ENaC
subunits into the apical membrane; second, the activation of existing
Na+ channels by regulatory proteins, by so-called
"aldosterone-induced proteins"; and third, the increase in the open
probability of Na+ channels (34). In primary
cultures of rabbit kidney connecting tubule and cortical collecting
duct (CNT and CCD, respectively) cells, the first phase of
aldosterone-stimulated transepithelial Na+ transport is
likely to be mediated by aldosterone-induced proteins. During the late
phase of aldosterone action, the threefold increase in apical
Na+ transport is accompanied by an increase in rbENaC mRNA
for all three subunits, but with only higher - and
-subunit
protein levels (5).
In addition to regulation of ENaC by aldosterone (5, 24, 25), long-term exposure to vasopressin also stimulates ENaC expression (8). Several other studies identified additional mechanisms involved in the regulation of ENaC activity, including changes in pH, ATP, Ca2+ concentrations, Na+ concentrations, and cell swelling (10, 13, 19). Notably, the role of these parameters in the short-term action of ENaC was studied. Furthermore, the role of these factors in aldosterone-induced stimulation of transepithelial Na+ transport has not been investigated. The aim of the present study was, therefore, to investigate the effect of the rate of apical Na+ entry on long-term effects of aldosterone. So far, the mechanisms by which ENaC synthesis is regulated in response to changes in the rate of apical Na+ entry are still poorly understood. Two forms of negative-feedback regulation by increased Na+ concentrations have been described (1, 33), namely, self-inhibition and feedback inhibition. Self-inhibition could be due to a direct interaction of extracellular Na+ with ENaC itself (28). In salivary duct cells it was found that Na+ channel activity does not change with increasing extracellular Na+ (19), whereas in frog skin Na+ channel activity is controlled by extracellular Na+ (11). On the other hand, feedback inhibition could also be mediated by an increase in intracellular Na+ concentration (19).
Primary cultures of rabbit CNT and CCD cells were used to study the
effect of changes in the driving force for apical Na+ entry
on aldosterone regulation of ENaC activity. In one protocol, primary
cultures were short-circuited to stimulate apical Na+
influx. In another protocol, monolayers were incubated overnight with
benzamil to block apical Na+ influx. In both protocols, the
benzamil-sensitive short-circuit current (Isc)
and -rbENaC (where rb is rabbit) protein levels were determined.
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MATERIALS AND METHODS |
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Primary cultures of rabbit kidney "cortical collecting
system."
Rabbit kidney CNT and CCD cells, hereafter referred to as the cortical
collecting system, were immunodissected from kidney cortex of New
Zealand White rabbits (±0.5 kg body wt) with the monoclonal antibody
R2G9 and set in primary culture on permeable filters (0.33 or 1.13 cm2; Costar, Cambridge, MA) as previous described in detail
(2). All experiments were performed with confluent
monolayers between 5 and 8 days after the cells were seeded. Sixteen
hours before the experiments, the monolayers were short-circuited by
flooding the monolayers with culture medium incubated with aldosterone (107 M, both sides) or benzamil (10
5 M,
apical) and combinations of these treatments.
Ussing chamber experiments.
For the measurement of transepithelial Isc,
filter cups (area 0.33 cm2) were routinely washed three
times with incubation medium containing (in mM) 140 NaCl, 2 KCl, 1 K2HPO4, 1 KH2PO4, 1 MgCl2, 1 CaCl2, 5 glucose, 5 L-alanine, and 10 HEPES-Tris (pH 7.4) and then mounted between two half-chambers and bathed at 37°C with incubation medium. The solutions bathing the monolayers were connected via agar bridges and Ag-AgCl electrodes to a voltage-clamp current amplifier
(Physiological Instruments, San Diego, CA), and the
Isc was recorded before and after the addition
of 105 M benzamil (apical side) The benzamil-sensitive
component of the Isc was used as an estimate of
transcellular sodium transport.
Measurements of extracellular ion concentrations. Confluent monolayers (0.33 cm2) were treated as described in the text. After 16 h of incubation, extracellular Na+, K+, and Ca2+ concentrations were determined by removing duplicate 20-µl samples from the apical and basolateral compartments. The Na+ and K+ contents of the samples were measured by flame photometry (Eppendorf FCM 6343, Hamburg, Germany). The Ca2+ concentration was measured using a colorimetric test kit (Boehringer, Mannheim, Germany).
Immunoprecipitation of -ENaC.
Confluent monolayers (1.33 cm2) were treated as described
in the text. Two hours before the end of the incubation period, filter cups were washed three times for 5 min with DMEM without methionine and
subsequently labeled at 37°C for 2 h by apical addition of 0.2 mCi/filter [35S]methionine (ICN Pharmaceuticals, Irvine,
CA). After incubation, the cells were washed, scraped, and
immunoprecipitated by incubation with affinity-purified
-ENaC
antisera as previous described in detail (5). The
immunoprecipitated proteins were resuspended in 25 µl of Laemmli
sample buffer and denatured for 5 min at 95°C. Next, 20 µl of the
samples were loaded on a 7% (wt/vol) SDS-polyacrylamide gel and
electrophoresed. The gel was stained for 10 min at 65°C with 0.25%
(wt/vol) Coomassie brilliant blue, 10% (vol/vol) acetic acid, and 50%
(vol/vol) methanol; destained twice for 10 min at 65°C with 7%
(vol/vol) acetic acid and 25% (vol/vol) methanol; rinsed in water; and
incubated twice for 10 min with DMSO and twice for 15 min with 20%
(wt/vol) 2,5-diphenyloxazole (Sigma Chemical, St. Louis, MO) in DMSO.
After two 5-min rinses in water, the gel was dried and exposed to a
film with an intensifying screen at
80°C. The relative amount of
35S incorporation was determined with Molecular Analyst
(Bio-Rad, Hercules, CA).
Chemicals. Benzamil was obtained from Research Biochemical International (Natick, MA). All other chemicals were obtained from Sigma. Benzamil and aldosterone were dissolved in ethanol, the final concentration of which never exceeded 0.1% (vol/vol). Aldosterone was added to the apical and basolateral sides, whereas benzamil was added to the apical side only.
Statistics. Results are given as means ± SE. For all experiments, statistical significance was determined by ANOVA; in the case of significance, individual groups were compared by contrast analysis according to Fisher. The level of statistical significance was set at P < 0.05.
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RESULTS |
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Effect of the rate of apical Na+ influx on the aldosterone-stimulated, benzamil-sensitive Isc. Primary cultures of rabbit CNT and CCD cells were used to determine whether changes in the rate of apical Na+ influx have an effect on transcellular Na+ transport, measured as the benzamil-sensitive Isc. Stimulation of the rate of apical Na+ influx was accomplished by short-circuiting the monolayers for 16 h by flooding the apical and basolateral compartments with culture medium to establish electrical contact. As a result, the apical membrane of the CCD and CNT cells would be hyperpolarized, which would stimulate the apical Na+ entry. Reduction of apical Na+ entry was accomplished by apical exposure of the monolayers to benzamil for 16 h.
Incubation of the monolayers with aldosterone (10
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Effect of extracellular ion concentrations on transepithelial
Na+ transport.
Next, we determined the Na+, K+, and
Ca2+ concentrations in the extracellular medium of control
and short-circuited monolayers untreated or treated with aldosterone.
Table 1 shows that after 16 h of
incubation, the apical Na+ concentration of untreated and
aldosterone-treated monolayers decreased from 140 to 82 and 59 mM,
respectively, whereas apical K+ concentration increased
from 5 to 32 and 38 mM, respectively. The apical Ca2+
concentration in unstimulated and stimulated conditions decreased from
1.0 to 0.36 and 0.47 mM, respectively. The influence of these extracellular ion concentrations on the modulation of the
aldosterone-induced, benzamil-sensitive Isc was
examined by mimicking the described circumstances. Na+ (80 mM) or 30 mM K+ in the medium during short-circuiting and
aldosterone treatment had no stimulating effect on benzamil-sensitive
Isc (50 ± 5 and 106 ± 27%,
respectively). Moreover, when the extracellular Ca2+
concentration was reduced by the Ca2+ chelator EGTA (0.8 mM) or the intracellular Ca2+ concentration by the
Ca2+ chelator
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
acetoxymethyl ester (10 µM) for 16 h, the Na+
channel activity did not change in aldosterone-stimulated,
short-circuited monolayers (117 ± 25 and 54 ± 31%,
respectively). Taken together, the extracellular Na+,
K+, or Ca2+ concentrations did not influence
the aldosterone-induced ENaC activity of rabbit CNT and CCD cells.
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Effect of the rate of apical Na+
influx on aldosterone-stimulated -rbENaC protein levels.
The aldosterone-stimulated rbENaC proteins were measured after the
driving force for apical Na+ entry was changed. The
-rbENaC protein levels were determined by radioactive
immunoprecipitation of this 97-kDa protein. The results of a
representative immunoblot of immunoprecipitated
-rbENaC from
[35S]methionine-labeled primary cultures of rabbit CNT
and CCD are shown in Fig. 2. Aldosterone
treatment for 16 h increased the
-rbENaC protein level by
310 ± 51% (Fig. 3). After 16-h
short-circuiting, the
-rbENaC protein level remained unaffected. The
inhibitory effect of chronically short-circuiting the monolayers on the
aldosterone-induced benzamil-sensitive Isc, as
shown above, was accompanied by a significant decrease in
aldosterone-stimulated
-rbENaC protein synthesis from 310 ± 51 to 115 ± 12% of control levels. Furthermore, in monolayers
exposed to benzamil for 16 h, the
-rbENaC protein synthesis was
increased to a protein level (282 ± 68%) comparable to that
found in aldosterone-induced monolayers. In monolayers in the combined
condition of short-circuiting, benzamil exposure, and aldosterone
exposure, the
-rbENaC protein synthesis was stimulated to the same
level (286 ± 45%). Thus, also on the protein level, benzamil
treatment overcame the inhibitory effect on aldosterone stimulation of
short-circuiting the monolayers.
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DISCUSSION |
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This study examines the influence of the rate of apical
Na+ entry on aldosterone regulation of transepithelial
Na+ transport. In primary cultures of rabbit kidney
cortical collecting system, aldosterone exposure stimulates an increase
in benzamil-sensitive Na+ transport, resulting from an
increase in - and
-ENaC protein synthesis (5). In
the present study, we have demonstrated that the aldosterone-stimulated
rbENaC transcription or translation process is blocked by a long-term
short-circuiting of the monolayers. It is likely that short-circuiting
the monolayers increases the intracellular Na+
concentration due to an increase in the apical Na+ influx
by hyperpolarization of the apical membrane (6, 9, 17).
Our study further shows that the rate of apical Na+ entry
has a significant effect on ENaC expression, because benzamil treatment
overrides the inhibitory effect of short-circuiting on
aldosterone-stimulated Na+ transport. This feedback
inhibition is mediated either by a decrease in
-rbENaC synthesis or
by an increase in
-rbENaC degradation.
The mechanisms by which intracellular Na+ concentration
might affect ENaC activity are unclear. Chronically short-circuiting the monolayers, and thereby increasing intracellular Na+
concentration, may inhibit the aldosterone-induced ENaC expression via
regulatory elements on the -,
-, and/or
-ENaC gene(s), for
example, via an as yet unidentified Na+-responsive element.
Many regulatory pathways, controlled by cytosolic Na+
concentration, are potentially involved in the feedback regulation of
ENaC. In salivary duct cells, Komwatana et al. (20, 21) have identified a G0 protein as the mediator of a
Na+-feedback system. This described model for feedback
regulation is as follows: cytosolic Na+ binds to an
intracellular Na+ receptor, activating the G0
protein, and the
-subunit of the G0 protein causes the
ubiquitine-protein ligase Nedd4 to ubiquinate and inactivate ENaC
(16). In Xenopus laevis oocytes,
Na+ feedback inhibition is present together with
Nedd4-dependent regulation of ENaC but does not require G protein
function (15). Nedd4 proteins contain WW domains, which
can bind to the PY motifs of
- and
-ENaC subunits and ubiquinate
the ENaC COOH termini, leading to endocytosis and degradation of ENaC.
This feedback-inhibition model could be applied to the present study in
the rabbit cortical collecting system. Short-circuiting of the
monolayers will result in a higher cytosolic Na+
concentration, and Na+ binds in a concentration-dependent
manner to an intracellular Na+ receptor, which activates
Nedd4 and leads to degradation of ENaC subunits. Mutations in the PY
motifs associated with Liddle syndrome, an inherited form of
salt-sensitive hypertension, also interfere with the feedback
regulation by intracellular Na+ (7, 13, 18).
Other feedback loops possibly involved in the downregulation of ENaC have also been studied in the past. Chalfant et al. (4) showed that in lipid bilayers rENaC currents were dependent on intracellular pH and were not influenced by changes in extracellular pH. In A6 cells (36) as well as in rat cortical collecting tubule (27), changes in intracellular pH correlate positively with changes in Na+ current and transepithelial conductance. An important finding in our study was that an extracellular pH between 7.4 and 5.6 is not a dominant factor in aldosterone-stimulated ENaC synthesis, because benzamil overcomes the inhibitory effect of short-circuiting on aldosterone-stimulated ENaC expression. In the short-circuiting situation, aldosterone-induced ENaC expression can also be decreased under the control of reduced ATP levels. The rise in intracellular Na+ will increase the energy used by the Na-K pump, leading to a decrease in ATP levels. Downregulation of ENaC as a result of increased demand for ATP by the Na-K pump is described by Frindt et al. (10). In addition, during benzamil exposure a rise in ATP can be involved in the stimulatory effect on ENaC expression. Another proposed factor involved in feedback inhibition is intracellular Ca2+. In the primary cultures of CNT and CCD there is no effect on the benzamil-sensitive Isc after buffering of the intracellular or extracellular Ca2+ concentrations of the short-circuited and aldosterone-exposed monolayers. The literature on experiments with increased cytoplasmic Ca2+ concentrations reports several discrepancies. In rat kidney, there is no direct effect of Ca2+ measured in inside-out patches, whereas in studies with vesicles of toad bladder and in rabbit cortical collecting tubules an increase in Ca2+ leads to a reduced amiloride-sensitive Na+ influx (9, 12).
One conclusion of our data is that an increase in cell volume, induced by increased Na+ influx, prevents the cell from reacting properly to aldosterone. Apparently, cell volume control has a higher priority then a response to aldosterone. Recently, the role of the cell volume-sensitive kinase sgk (serine-threonine kinase) in ENaC regulation has also been described (22, 26, 29). Sgk is rapidly and strongly upregulated by aldosterone in rat cortical collecting duct. In addition, coexpression of sgk with ENaC in X. laevis oocytes stimulated ENaC activity about sevenfold. The sgk transcription level correlates negatively with cell volume (35). Cell swelling-associated degradation of sgk also provides a possible explanation for the inhibiton of aldosterone-induced Na+ transport, which we observed in short-circuited cells. Blocking of Na+ entry by benzamil may lead to cell shrinkage, and this could stimulate the accumulation of sgk and thereby ENaC activity. It is of interest to note that modulation of Na+ influx by short-circuiting A6 cells in the absence of aldosterone has an effect opposite to what we report here for rabbit primary cultures of CNT and CCD cells in the presence of aldosterone. Rokaw et al. (31) showed that decreasing Na+ influx decreases Isc and increasing Na+ influx increases Isc. These observations were made in culutres in the absence of aldosterone. Therefore, intracellular Na+ concentration may have dual effects depending on the absence or presence of aldosterone.
In conclusion, in the present study we have demonstrated that in primary cultures of the rabbit cortical collecting system the aldosterone transcription-translation process can be inhibited by chronically short-circuiting the monolayers. Chronic benzamil treatment can overcome this inhibitory effect. The obvious explanation is feedback inhibition by an increase in the intracellular Na+ concentration as a result of hyperpolarization of the apical membrane. Further experiments are needed to delineate the molecular mechanism behind this feedback inhibition by intracellular Na+.
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ACKNOWLEDGEMENTS |
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We thank T. Koks for contributing to the Ussing chamber experiments.
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FOOTNOTES |
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This work was supported by Dutch Kidney Foundation Grant C94.1348.
Address for reprint requests and other correspondence: R. J. M. Bindels, Department of Cell Physiology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands (E-mail: ReneB{at}sci.kun.nl).
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. Section 1734 solely to indicate this fact.
Received 13 December 2000; accepted in final form 17 May 2001.
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