1 Department of Molecular Genetics, Biochemistry and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524; and 2 Department of Biomedical Sciences, College of Veterinary Medicine and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
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ABSTRACT |
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Upregulation of the colonic
H+-K+- ATPase (cHKA) during
hyperaldosteronism suggests that it functions in both K+
conservation and electrogenic Na+ absorption in the colon
when Na+-conserving mechanisms are activated. To test this
hypothesis, wild-type (cHKA+/+) and
cHKA-deficient (cHKA/
) mice were fed
Na+-replete and Na+-restricted diets and their
responses were analyzed. In both genotypes, Na+ restriction
led to reduced plasma Na+ and increased serum aldosterone,
and mRNAs for the epithelial Na+ channel (ENaC)
- and
-subunits, channel-inducing factor, and cHKA were increased in
distal colon. Relative to wild-type controls, cHKA
/
mice on a Na+-replete diet
had elevated fecal K+ excretion. Dietary Na+
restriction led to increased K+ excretion in knockout but
not in wild-type mice. The amiloride-sensitive, ENaC-mediated
short-circuit current in distal colon was significantly reduced in
knockout mice maintained on either the Na+-replete or
Na+-restricted diet. These results demonstrate that cHKA
plays an important role in K+ conservation during dietary
Na+ restriction and suggest that cHKA-mediated
K+ recycling across the apical membrane is required for
maximum electrogenic Na+ absorption.
Atp1al1; potassium absorption; sodium absorption; hydrogen secretion
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INTRODUCTION |
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THE COLONIC
H+-k+-atpase (cHKA), a member of the
P-type family of ion transport ATPases that was cloned from distal
colon (11), is expressed in apical membranes of distal
colon surface cells (19, 27, 33). The existence of an
H+-K+-ATPase in distal colon, or possibly two
H+-K+-ATPases (1), was first
indicated by physiological studies showing a linked pathway for
H+ secretion and K+ absorption across the
apical membrane of distal colon epithelial cells that was
Na+ independent and sensitive to vanadate (12, 18,
23, 38, 39, 44). Expression studies using Xenopus
oocytes demonstrated that cHKA is indeed an
H+-K+-ATPase (6, 10), although
there are data showing that the enzyme can substitute Na+
for H+ and NH/
mice exhibit a defect in
colonic K+ conservation when fed either a control diet or a
K+-depleted diet (30). Dietary K+
restriction does not affect cHKA mRNA, protein, or activity in colon
(20, 35); however, in several models of
hyperaldosteronism, including dietary Na+ restriction
(35), treatment with aldosterone (20), and
targeted mutation of the NHE3 Na+/H+ exchanger
(36), cHKA mRNA is sharply induced.
In the rat distal colon, dietary Na+ restriction or
treatment with aldosterone causes a switch in Na+ transport
from predominantly electroneutral absorption via coupled Na+/H+ and
Cl/HCO
The electrogenic absorption of Na+ from the lumen of the
colon requires either the absorption of an anion or the secretion of a
cation to maintain the appropriate electrochemical gradient across the
apical membrane. For this reason, recycling of K+ that is
secreted across the apical membrane may be critical for maximum
electrogenic Na+ absorption via the epithelial
Na+ channel (ENaC). Thus we hypothesized that the induction
of cHKA during dietary Na+ restriction or other conditions
in which aldosterone levels are elevated may allow an increased rate of
K+ recycling across the apical membrane, thereby
facilitating Na+ absorption. If so, then the loss of cHKA
should impair both K+ conservation and electrogenic
Na+ absorption. To test these hypotheses, we analyzed
colonic Na+ and K+ conservation and
electrogenic Na+ absorption in wild-type and
cHKA/
mice. The results demonstrate that the
loss of cHKA impairs both K+ conservation and electrogenic
Na+ absorption during dietary Na+ restriction.
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METHODS |
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Maintenance of mice and genotype analysis. Generation of cHKA-deficient mice was described previously (30). For the present study, the targeted null mutation was bred onto a C57BL/6 background. Mice were maintained in a pathogen-free barrier facility with free access to standard mouse chow and water until the time of the study.
Genotyping was performed by PCR analysis of genomic DNA isolated from tail biopsies. The PCR reaction used two cHKA gene-specific primers and one neomycin resistance gene-specific primer. The 5' cHKA primer (5'-CTGGAATGGACAGGCTCAACG-3') in conjunction with the 3' cHKA primer (5'-GTACCTGAAGAGCCCCTGCTG-3') amplified a 154-bp fragment of exon 20 from the wild-type allele. The 5' cHKA primer and the neomycin resistance gene primer (5'-CTGACTAGGGGAGGAGTAGAAGG-3') amplified a 298-bp fragment from the mutant allele that contains portions of exon 20 and the neomycin resistance gene. The PCR genotyping strategy and an example of the PCR amplifications are shown in Fig. 1.
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Western blot analysis.
The distal colon was removed from two cHKA+/+
and two cHKA/
mice and homogenized in 2 ml
sucrose buffer [5 mM Tris, pH 7.5, 0.25 M sucrose, 2 mM EDTA, and 1 mM
phenylmethylsulfonyl fluoride (PMSF)]. A 750-µl aliquot was
centrifuged at 11,000 rpm for 30 min at 4°C. The supernatant was
placed in a fresh tube and centrifuged at 50,000 rpm for 60 min at room
temperature. The membrane pellet was resuspended in buffer B (50 mM
HEPES, pH 7.6, 1 mM EDTA, and 1 mM PMSF). A portion of the membrane
preparation (10 µl) was separated by electrophoresis in a 10%
denaturing polyacrylamide gel and transferred to a nylon membrane. The
primary antibody against cHKA (4) (a generous gift from
Drs. Thomas DuBose and Juan Codina) was incubated with the membrane at
a 1:1,000 dilution for 2 h. The secondary antibody was incubated
at a 1:20,000 dilution for 1 h. Detection was performed with the
SuperSignal kit (Pierce, Rockford, IL) according to the manufacturer's
protocol. The protein on the membrane was then stained with Ponceau
solution (Sigma) to confirm equal loading between lanes.
Dietary Na+ restriction studies.
Studies were performed on age- and sex-matched adult
cHKA+/+ and cHKA/
mice. Mice were fed a control diet containing 1% NaCl, followed by a
diet containing 0.01% NaCl (Harlan Teklad, Madison, WI), and urine and
feces were collected daily. Urine volume was measured, and
Na+ and K+ content were determined by flame
photometry as described previously (30) and presented as
3-day averages. Feces from three consecutive days were pooled, weighed,
dissolved in 0.75 N nitric acid, and centrifuged. Determination of
fecal Na+ and K+ content was performed by flame
photometry of the supernatant as described previously
(30).
Determination of blood pH, gases, and electrolytes and serum aldosterone. Blood (50 µl) was collected from the tail vein of conscious mice and analyzed immediately for acid/base status, blood gases, and plasma electrolytes using a Chiron Diagnostics model 348 pH/blood gas analyzer (30). These analyses were performed at the end of both the control diet period and the Na+-restricted diet period. Serum aldosterone concentrations were also determined at the end of each period using a 125I radioimmunoassay as previously described (36).
Northern blot analyses.
Total RNA from the kidneys of three animals in each experimental group
and total RNA from proximal and distal colon of two animals in each
group were isolated and pooled. Total RNA (10 µg) was denatured,
separated by agarose gel electrophoresis, and transferred to a nylon
membrane. Hybridization was performed as described previously
(36) using cDNA probes for the -subunit of cHKA; the
1-subunit of the Na+-K+-ATPase;
channel-inducing factor (CHIF); the
-,
-, and
-subunits of
ENaC; and the mouse L32 ribosomal protein (as a loading control).
Bioelectric measurements.
Transepithelial current measurements in the distal colon of
cHKA+/+ and cHKA/
mice were performed under short-circuit (Isc)
conditions in Ussing chambers as described (3). Freshly
isolated tissues were mounted in voltage-clamped Ussing chambers and
were bathed in Krebs-Ringer-HCO
Statistics. Statistical significance was calculated by single-factor ANOVA, ANOVA-protected Bonferroni's t-test, or paired t-test as appropriate. Data are presented as means ± SE.
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RESULTS |
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Dietary Na+ restriction was carried out using
wild-type and cHKA/
mice, which were housed
individually in metabolic cages. The mice received food containing 1%
NaCl during the 6-day control period (days 1-6) and
0.01% NaCl during the 12-day period of Na+ restriction
(days 7-18). Urine and feces were collected and
analyzed, and at the conclusion of each dietary period, blood was
collected for analysis of blood gases, pH, plasma electrolytes, and
serum aldosterone. Northern blot analyses of kidney and intestinal
segments of Na+-replete and Na+-restricted mice
were performed, and a separate group of Na+-replete and
Na+-restricted mice were used for analysis of
Isc in distal colon.
Body weights.
At the beginning of the study,
cHKA+/+ and
cHKA/
mice had similar body weights
(23.8 ± 1.5 and 23.2 ± 1.1 g, respectively). The mice
were also weighed at the end of the control diet period (day 6: cHKA+/+, 23.2 ± 1.1 g;
cHKA
/
, 22.7 ± 1.1 g), at the
midpoint of the Na+-restricted period (day
12: cHKA+/+, 23.8 ± 1.3 g;
cHKA
/
, 22.7 ± 1.1 g), and at the
end of the experiment (day 18:
cHKA+/+, 24.4 ± 1.4 g;
cHKA
/
, 23.3 ± 1.1 g). There
were no significant differences in body weight for either genotype
during the 18-day study, nor were there any significant
differences in body weight between genotypes at any time point.
Western blot analysis of cHKA protein in distal colon of wild-type
and cHKA/
+mice.
To confirm the effectiveness of the gene-targeting strategy, membranes
were isolated from the distal colons of Na+-restricted
wild-type and cHKA
/
mice and examined by
Western blot analysis. An antibody directed against cHKA identified a
~110-kDa protein in cHKA+/+ distal colon, but
only a trace band was seen in the same position in
cHKA
/
distal colon (Fig.
2). The faint band seen in the knockout
lanes may have been due to nonspecific hybridization, because it
corresponds in position to a strong protein band observed in all lanes
after staining with Ponceau solution (not shown). Alternatively, it may
represent trace levels of a mutant protein, lacking some of the COOH
terminal transmembrane domains, that could be produced from the
aberrant cHKA transcripts.
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Urinary and fecal excretion of K+ and
Na+.
As shown in Fig. 3A, urinary
K+ excretion was similar for Na+-replete
cHKA+/+ (1,199 ± 113 µmol/3 days) and
cHKA/
(1,143 ± 89 µmol/3 days) mice
but differed significantly following Na+ restriction
(932 ± 88 and 754 ± 75 µmol/3 days, respectively; P < 0.01). Urinary Na+ excretion (Fig.
3B) was similar for cHKA+/+ and
cHKA
/
mice during the control period
(734 ± 122 and 855 ± 132 µmol/3 days, respectively) but
decreased by ~99%, to 7.46 ± 0.85 and 6.96 ± 1.57 µmol/3 days, respectively, following Na+ restriction.
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Plasma electrolytes and serum aldosterone.
Plasma electrolytes and systemic acid/base status were analyzed at the
end of each dietary period (Table 1).
Serum Na+ concentrations in Na+-replete
cHKA+/+ and cHKA/
mice were 149.1 ± 0.5 mM and 150.0 ± 0.6 mM, respectively.
Serum Na+ did not differ significantly between the two
genotypes on either diet; however, both groups of mice became
hyponatremic after 12 days of Na+ restriction, with serum
Na+ of 146.8 ± 0.7 mM in wild-type mice
(P = 0.034) and 146.9 ± 0.4 mM in the knockout
(P < 0.01). Serum Cl
concentrations did
not differ significantly between cHKA+/+ and
cHKA
/
mice on a Na+-replete
diet. During Na+ restriction, serum Cl
did
not change in the knockout mice but was slightly elevated in wild-type
mice (P = 0.024; this is most likely a statistical anomaly). Serum K+, pH, and HCO
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Northern blot analysis of kidneys and colon.
Northern blot hybridization was performed using kidney RNA from
Na+-replete and Na+-restricted mice (Fig.
6, left). A previous study
showed that cHKA mRNA is expressed at almost undetectable levels in
kidneys of K+-replete wild-type mice but is sharply induced
by K+-depletion (30). However, we observed no
signal for cHKA mRNA in kidneys of Na+-replete mice of
either genotype, and there was no evidence of cHKA induction in
response to Na+ restriction. Na+ restriction
had no apparent effect on kidney mRNA levels for the ENaC subunits,
CHIF, or the Na+-K+-ATPase
1-subunit.
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Isc in the distal colon of
Na+-restricted
cHKA+/+ and cHKA/
mice.
In an initial set of experiments designed to test the concentrations of
amiloride needed to fully inhibit ENaC, we measured transepithelial
current in the distal colon of Na+-restricted
cHKA+/+ and cHKA
/
mice under short-circuit conditions in the absence of amiloride and
then in the presence of 1 µM and then 50 µM amiloride. Dietary Na+ restriction was used to enhance the magnitude of the
ENaC-mediated currents. The basal Isc in
cHKA
/
colon was significantly lower than
that in cHKA+/+ colon (
39.1 ± 6.7 µA/cm2 and
193.2 ± 14.1 µA/cm2,
respectively; P < 0.01; Fig.
7). After the luminal addition of 1 µM
amiloride, the Isc decreased in both groups
(cHKA
/
,
13.7 ± 3.3 µA/cm2; cHKA+/+,
59.7 ± 6.9 µA/cm2; P < 0.01). Addition of 50 µM amiloride led to a further reduction in the
Isc (cHKA
/
, 0.5 ± 1.2 µA/cm2; cHKA+/+, 22.7 ± 4.1 µA/cm2; P < 0.01). In subsequent
experiments, 50 µM amiloride was used to inhibit the ENaC-mediated
current.
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DISCUSSION |
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Studies with cHKA/
mice have shown that
the cHKA plays an important role in K+ conservation in the
colon during dietary K+ restriction (30),
although its mRNA is not induced in the colon under these conditions
(35). K+ restriction and the resulting low
serum aldosterone levels cause a reduction in apical K+
secretion; hence, there is much less K+ to recover and
normal levels of the pump are apparently sufficient to reduce fecal
K+ losses to very low levels (30). In
contrast, cHKA mRNA, protein, and activity in distal colon are
increased in response to dietary Na+ deprivation or
elevated serum aldosterone levels (20, 35), suggesting
that its activity might be particularly important under conditions in
which electrogenic Na+ absorption predominates in the colon
(22). In the current study, we used cHKA knockout mice to
examine the role of the pump in K+ conservation during
dietary Na+ restriction and to determine whether its
absence affects the rate of electrogenic Na+ absorption.
Dietary Na+ restriction or treatment with aldosterone has
been shown to stimulate NaCl absorption in the rat proximal colon via
coupled electroneutral Na+/H+ and
Cl/HCO
cotransporter
(42), both of which mediate K+ uptake across
the basolateral membrane. Nevertheless, it was reasonable to anticipate
that recycling of secreted K+ via the colonic
H+-K+-ATPase, which would be expected to
enhance the apical K+ gradient, might also be required for
maximum electrogenic Na+ absorption.
Neither cHKA+/+ nor
cHKA/
mice fed a 0.01% NaCl diet exhibited
overt pathology, morbidity, or loss of body weight. Serum
K+, Cl
, and HCO
1-subunit, which
has been shown to associate with the cHKA
-subunit in vivo (4,
26). CHIF, which activates a K+ current
(2), was induced only in distal colon. In both proximal and distal colon, ENaC mRNAs were expressed at similar levels in
Na+-replete cHKA+/+ and
cHKA
/
mice, and ENaC
- and
-subunit
mRNAs were sharply induced in both segments during Na+
restriction. These results demonstrated that dietary Na+
restriction in the mouse had the expected effects on Na+
homeostasis and serum aldosterone and that it modified ion transporter mRNA expression in cHKA+/+ and
cHKA
/
colon in a manner similar to that
reported for rat colon (2, 13, 20, 35, 43).
When fed a control diet containing 1% NaCl, the K+ content
of the feces of cHKA/
mice was ~50%
higher than for cHKA+/+ mice. During the
Na+ restriction period, wild-type mice maintained the same
fecal K+ levels as observed on the Na+-replete
diet, but the fecal K+ content of the knockout increased to
a level 2.8-fold greater than that of wild-type mice. These data
provide direct confirmation of the hypothesis that cHKA plays an
important role in colonic K+ conservation not only during
dietary K+ restriction, as shown previously
(30), but also during dietary Na+ restriction.
This suggests that part of the biological rationale for the induction
of cHKA in colon by Na+ restriction or under conditions in
which serum aldosterone is elevated, as observed previously in rat and
mouse colon (20, 35, 36), is to recover the K+
being secreted under these conditions (16).
The Na+ content of the feces of both
cHKA+/+ and cHKA/
mice decreased by ~90% during the Na+ restriction
period, although it remained slightly higher in
cHKA
/
mice than in
cHKA+/+ mice. To analyze Na+
transport in the distal colon of cHKA+/+ and
cHKA
/
mice, Isc in
colons of Na+-replete and Na+-restricted mice
were analyzed. These experiments showed that the amiloride-sensitive
Na+ current in both the Na+-replete and
Na+-restricted cHKA
/
colon was
substantially less than that observed in the corresponding cHKA+/+ colon. Although ENaC activity was
induced by Na+ depletion in both genotypes, the
Na+ current present in Na+-restricted
cHKA
/
colon was essentially the same as that
observed in Na+-replete cHKA+/+
colon and ~25% of that in Na+-restricted
cHKA+/+ colon (see Fig. 8). But why would the
loss of cHKA cause a reduction in electrogenic Na+
absorption? One possibility, as suggested by others (22),
is that cHKA functions as a K+-recycling mechanism to
maintain K+ secretion and a favorable membrane potential
for electrogenic Na+ absorption. Similar ion recycling
mechanisms have been observed in other systems. For example, gene
knockout studies showed that a reduction in the levels of the
Na+-K+-ATPase
2-isoform, but not the
1-isoform, enhances cardiac contractility and Ca2+
loading of cardiac myocytes (20). It was concluded that
regulation of subsarcolemmal Na+ concentrations by the
2-isoform controls the activity of the Na+/Ca2+ exchanger, with the resulting
alteration in intracellular Ca2+ affecting cardiac
contractility (21). In another recent example, the
extrusion of H+ via an apical
Na+/H+ exchanger was shown to reduce the
subapical H+ concentration in colonocytes, thereby creating
a pH microclimate that stimulated the uptake of short-chain fatty acids
(17). Finally, it is well established that recycling of
K+ by the renal outer medullary K+ channel is
critical for activity of the apical
Na+-K+-2Cl
cotransporter of the
thick ascending limb and for accompanying paracellular transport of
Na+ (37). The results of the present study
indicate that K+ absorption by the colonic
H+-K+-ATPase reduces luminal K+
concentrations and are consistent with the possibility that it serves
as a K+-loading mechanism that increases subapical
K+ concentrations. If this hypothesis is correct, then the
resulting transmembrane K+ gradient would enhance
electrogenic K+ secretion, thereby contributing to the
electrical potential needed for maximum electrogenic Na+ absorption.
Given that ENaC-mediated Na+ currents in
cHKA/
distal colon were much less than in
wild-type distal colon, it was surprising that
cHKA
/
mice exhibited only a mild increase in
fecal Na+ excretion, even when maintained on a
Na+-depleted diet. A possible explanation for this
discrepancy is that apical Na+/H+ exchange
activity is higher in cHKA
/
distal colon
than in wild-type distal colon, thereby compensating for the reduction
in ENaC activity. Our measurements of ENaC activity do not allow an
estimation of the relative amounts of Na+ being absorbed
via the electroneutral process of coupled
Na+/H+ and
Cl
/HCO
-subunit (40),
raising the intriguing possibility that it might interact with and
affect the activity of cHKA. The conditions under which CHIF is
induced, such as during dietary Na+ depletion or in
diarrheal states such as in the NHE3-deficient mouse, are those in
which the H+/K+ exchange mode would likely play
an important role in the recovery HCO
Although our primary objective was to investigate the role of cHKA in K+ conservation and electrogenic Na+ absorption in the colon, we were also interested in determining whether dietary Na+ restriction might affect renal Na+ handling. cHKA is expressed at very low levels in rat kidney under K+-replete conditions (11), but its mRNA and protein are induced by K+ deprivation (3, 25), a condition in which aldosterone levels are low. Although cHKA mRNA is sharply induced in mouse kidney by K+ deprivation (30), it was not induced by Na+ deprivation, nor was there any significant increase in urinary Na+ excretion in the knockout. Our results are consistent with previous experiments showing that aldosterone does not induce cHKA mRNA in kidney, as it does in colon (20). These data suggest that cHKA is not required for Na+ conservation in the mouse kidney during dietary Na+ restriction.
As illustrated in the model shown in Fig.
9, the current and previous studies of
cHKA suggest that it carries out, in concert with other transporters,
at least two important physiological functions in the colon. A role in
K+ conservation was clearly demonstrated by the earlier
observation that cHKA/
mice exhibit greater
fecal K+ excretion and become more hypokalemic than
wild-type mice when maintained on a K+-deficient diet
(30), and the results of the present study show that cHKA
is also important for K+ conservation during dietary
Na+ restriction. Depending on whether or not it is coupled
with the apical Cl
/HCO
/HCO
/HCO
, and HCO
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ACKNOWLEDGEMENTS |
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We thank Drs. Thomas DuBose and Juan Codina for the generous gift of the cHKA antibody used in this study.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-50594 and DK-48816.
Address for reprint requests and other correspondence: G. E. Shull, Dept. of Molecular Genetics, Biochemistry and Microbiology, Univ. of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML 524, Cincinnati, OH 45267-0524 (E-mail: shullge{at}ucmail.uc.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. Section 1734 solely to indicate this fact.
Received 5 March 2001; accepted in final form 3 July 2001.
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