1 Department of Surgery, Stanford University, Stanford 94305; and 2 Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521
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ABSTRACT |
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The
aquaporin-4 (AQP4) water channel has been proposed to play a role in
gastric acid secretion. Immunocytochemistry using anti-AQP4
antibodies showed strong AQP4 protein expression at the basolateral
membrane of gastric parietal cells in wild-type (+/+) mice. AQP4
involvement in gastric acid secretion was studied using transgenic null
(/
) mice deficient in AQP4 protein.
/
Mice had grossly normal
growth and appearance and showed no differences in gastric morphology
by light microscopy. Gastric acid secretion was measured in
anesthetized mice in which the stomach was luminally perfused (0.3 ml/min) with 0.9% NaCl containing [14C]polyethylene
glycol ([14C]PEG) as a volume marker. Collected effluent
was assayed for titratable acid content and [14C]PEG
radioactivity. After 45-min baseline perfusion, acid secretion was
stimulated by pentagastrin (200 µg · kg
1
· h
1 iv) for 1 h or histamine (0.23 mg/kg iv) + intraluminal carbachol (20 mg/l). Baseline gastric acid secretion
(means ± SE, n = 25) was 0.06 ± 0.03 and
0.03 ± 0.02 µeq/15 min in +/+ and
/
mice, respectively.
Pentagastrin-stimulated acid secretion was 0.59 ± 0.14 and
0.70 ± 0.15 µeq/15 min in +/+ and
/
mice, respectively. Histamine plus carbachol-stimulated acid secretion was 7.0 ± 1.9 and 8.0 ± 1.8 µeq/15 min in +/+ and
/
mice, respectively.
In addition, AQP4 deletion did not affect gastric fluid secretion, gastric pH, or fasting serum gastrin concentrations. These results provide direct evidence against a role of AQP4 in gastric acid secretion.
water transport; stomach; gastrin; transgenic mice
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INTRODUCTION |
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AQUAPORIN-4 (AQP4; mercurial insensitive water channel) is a water-selective transporting protein that was initially cloned from rat lung (9), and, subsequently, homologous cDNAs were isolated from the rat brain and stomach and various mouse and human tissues (11, 19, 34). Immunocytochemistry showed rat AQP4 protein expression at the basolateral membrane of parietal cells in the stomach, as well as in the kidney collecting duct, brain ependyma and astroglia, skeletal muscle sarcolemma, and epithelial cells in the trachea, airways, and colon (6, 7). AQP4 has been shown to be a component of "orthogonal arrays of particles" (OAPs), characteristically square intramembrane particle arrays visualized by freeze-fracture electron microscopy (22, 28, 32). OAPs have been observed at sites of AQP4 expression, including gastric parietal cells (2). Functional analysis showed that AQP4 has substantially higher intrinsic water permeability than other aquaporins (35) and that AQP4 water permeability is not inhibited by mercurial compounds because it lacks a critical cysteine expressed in other aquaporins (24). On the basis of the tissue localization and functional information, it was proposed that AQP4 has a physiological role in gastric acid secretion (5, 23, 30).
Recently, transgenic AQP4-deficient knockout (/
) mice were
generated by targeted gene disruption (16). The
/
mice
have grossly normal development, growth, and appearance. Functional analysis of kidney collecting duct
/
mice has revealed decreased osmotically driven water permeability (4). Phenotype
analysis of the
/
mice has revealed a mild defect in urinary
concentrating ability (16), a blunted brain swelling
response to water intoxication and ischemic stroke (17),
and decreased airspace-capillary water permeability in lung
(25). An extensive study of skeletal muscle function
showed no abnormalities in AQP4-deficient mice, despite selective AQP4
expression in plasmalemma of fast-twitch skeletal muscle fibers
(35).
The purpose of this investigation was to test the hypothesis that AQP4
is required for gastric acid secretion. The involvement of AQP4 in
gastric acid physiology was suggested by its specific expression in
gastric parietal cells, the cell type responsible for acid production
in the stomach and apparent regulation of OAP structure by pentagastrin
(2). There are a number of possible mechanisms by which
AQP4 could facilitate gastric acid secretion, such as increased
glandular fluid secretion, which prevents accumulation of secreted
H+ (5), or an AQP4 transporting role in the
parietal cells, such as direct solvent-solute coupling or
CO2 transport. CO2 transport by the homologous
water channel AQP1 has been reported (21); however, recent
experiments (33) provided direct evidence against a
physiologically important role for AQP1-mediated CO2
transport. In this study, we compare basal and hormone-stimulated
gastric acid production and fluid secretion in wild-type (+/+) and AQP4 /
mice, as well as serum gastrin concentrations and gastric fluid pH.
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METHODS |
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Transgenic mice.
Studies were performed in 25- to 35-g +/+ and AQP4 /
mice in a CD1
genetic background. The AQP4
/
mice were generated by targeted gene
disruption as described previously (16). Genotype analysis
of tail DNA was performed by PCR when mice were 5 days old. The
investigators were blinded to genotype for gastric acid secretion
studies, serum gastrin measurements, and immunohistochemistry. Animal
protocols were approved by the Stanford University institutional administrative panel on laboratory animal care.
Surgical procedures.
Mice were fasted overnight but given free access to 10% dextrose in
water. Mice were anesthetized with intraperitoneal pentobarbital sodium
(5 mg/kg). An overhead lamp and heating pad were used to maintain core
body temperature at 36-38°C. A right jugular vein catheter
(PE-10 tubing, Becton Dickinson, Sparks, MD) was inserted via a right
neck cutdown, and normal saline was infused at a rate of 10 ml · kg1 · h
1. Via a midline abdominal
incision, a ligature was placed at the esophagogastric junction with
care not to injure the vagus nerve trunks. Via a duodenotomy, a flared
segment of PE-240 tubing to be used for inflow of perfusate was passed
into the stomach and through the wall of the fundus along the greater
curve. A PE-240 outflow catheter was passed into the duodenotomy just
proximal to the pylorus. Both catheters were secured in place with 6-0 silk suture. Stomachs were flushed with warmed saline until the effluent was clear, followed by perfusions with 0.9% NaCl containing 5 g/l polyethylene glycol (PEG; mol wt 3,000; Sigma, St. Louis, MO) and 5 µCi/l [14C]PEG (0.3 ml/min). After an initial 15-min
stabilization period, effluent fluid was collected in 15-min intervals.
After 45 min, pentagastrin (200 µg · kg
1
· h
1) was continuously infused intravenously. Effluent
was collected for 75 min. In some experiments, intravenous histamine
(0.23 mg · kg
1 · ml
1) plus
intraluminal carbachol (added to the luminal perfusate, 20 mg/l) were
added to pentagastrin to induce maximal gastric acid stimulation.
Measurement of gastric acid secretion.
Titratable acid content in pregastric infusate and postgastric effluent
were measured by manual titration using sodium hydroxide (103 M) and a pH meter (Cole-Parmer Instrument, Vernon
Hills, IL). All samples were run in triplicate, and the average was
reported. The difference in titratable acid content between the
infusate and effluent indicated the total acid secreted into the
stomach during each 15-min interval.
Measurement of gastric fluid secretion.
Aliquots (0.5 ml) of infusate and effluent were assayed for
14C radioactivity in triplicate by liquid scintillation
counting (LS 6000SC, Beckman Instruments, Brea, CA). The amount of net water flux (Jw) within the gastric lumen was
determined as follows (3): Jw = V(1[14C]PEGinfusate/[14C]PEGeffluent)/W,
where V is the perfusion rate and W is the excised stomach
dry weight in grams.
Gastric pH measurements. After overnight feeding, mice were killed at 8 AM, and gastric fluid was immediately sampled for pH determination using strips of pH paper (pHydrion, Brooklyn, NY).
Serum gastrin measurements.
Mice were fasted overnight with free access to water. Next, mice were
anesthetized with intraperitoneal pentobarbital sodium (5 mg/kg) and
then exsanguinated via median sternotomy followed by transection of the
inferior vena cava. Blood was immediately collected from the chest
cavity and centrifuged at 3,000 rpm for 5 min. Serum was collected and
frozen at 20°C. Frozen serum samples were sent to the University of
California Los Angeles CURE Center for gastrin RIA.
Morphology and immunocytochemistry. Mice were anesthetized, and stomachs were rapidly excised and incubated in 1% formalin for 4 h. Rings of full-thickness stomach were then placed into PBS plus 30% dextrose at 4°C for 12 h. Tissues were then imbedded in OCT compound, and five 1-µm cryostat sections were obtained. Slides were prepared as previously reported (6). Using hematoxylin and eosin-stained slides, we counted the number of parietal cells per gastric pit. Double-labeled immunohistochemistry was performed using goat anti-rabbit FITC conjugated IgG (Life Technologies, Gaithersburg, MD) against rabbit anti-rat AQP4 antibodies and goat anti-mouse Texas red-conjugated IgG (Jackson Immunoresearch Labs, West Grove, PA) against monoclonal H+-K+-ATPase antibody (MBL International, Watertown, MA). Dual fluorescence images were obtained using a Molecular Dynamics multiprobe 2010 CLSM confocal microscope interfaced to a Silicon Graphics Indigo2 workstation.
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RESULTS |
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The morphology of gastric pits and expression of AQP4 and
H+-K+-ATPase were assessed. By light and
fluorescence microscopy, there were no gross differences in morphology
or in the number of parietal cells within the gastric pits. Figure
1 shows the distribution of AQP4 and
H+-K+-ATPase along a gastric pit and within a
parietal cell of +/+ and /
mice.
H+-K+-ATPase is uniformly distributed
throughout the length of a gastric pit in mice of both genotypes. In
+/+ mice, AQP4 is more heavily concentrated at the base with no
detectable expression in the neck of the gastric pit. No AQP4 staining
was seen in the
/
mice.
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To determine if AQP4 is involved in parietal cell acid secretion,
several secretory agonists were used to increase gastric acid output in
+/+ and /
mice. Figure 2 shows the
basal, pentagastrin-stimulated, and pentagastrin, carbachol, and
histamine-stimulated gastric acid outputs of +/+ and
/
mice. Basal
acid secretion was not different between +/+ and
/
mice (0.06 ± 0.03 vs. 0.03 ± 0.02 µeq/15 min, respectively,
n = 25). Acid secretion was increased during
pentagastrin infusion but not different in +/+ vs.
/
mice
(0.59 ± 0.14 vs. 0.70 ± 0.15 µeq/15 min). Addition of
luminal carbachol and intravenous histamine resulted in substantially greater acid secretion, which was not different in +/+ vs.
/
mice
(7.0 ± 1.9 vs. 8.0 ± 1.8 µeq/15 min, n = 25). These data suggest that AQP4 is not involved in basal or
agonist-stimulated gastric acid output.
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Because aquaporins have been implicated in transepithelial water
transport in several epithelial tissues (15-17,
20), Jw was compared in +/+ and
/
mice. Figure 3 shows basal,
pentagastrin-stimulated, and pentagastrin, histamine, and
carbachol-stimulated Jw in +/+ and
/
mice.
Although there was a trend toward greater negative Jw (net secretion) in the
/
mice, there were
no significant differences. This absence of a difference in water flux
suggests that AQP4 is not important in the total water flux in the
stomach under basal and stimulated conditions.
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To determine whether AQP4 deletion affected the pH of gastric fluid
under normal physiological conditions, gastric fluid was sampled in the
morning after overnight feeding and pH was measured immediately using
pH paper. In +/+ and /
mice, pH was consistently <1.5, indicating
that AQP4 deletion did not prevent the generation of a very low pH in
gastric fluid.
Transgenic mice lacking gastrin/CCK-B receptors have elevated serum
gastrin concentrations (14, 18,
31). To determine if AQP4 deletion results in altered
serum gastrin levels, serum was collected from fasted +/+ and /
mice. Figure 4 shows that fasting serum
gastrin levels for +/+ and
/
mice were 43 ± 9 and 30 ± 6 pg/ml, respectively (not significant, n = 16). The normal serum gastrin in
/
mice supports the conclusion that AQP4
deletion does not alter in vivo gastric acidification.
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DISCUSSION |
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The goal of this study was to determine whether AQP4 is involved
in gastric acid and fluid secretion. This study was motivated by the
strong, selective expression of AQP4 in gastric parietal cells, and as
mentioned earlier, the diverse set of phenotypic abnormalities
documented in AQP4 /
mice. Immunolocalization studies here in mice
confirmed AQP4 protein expression in parietal cells at the base of
gastric pits, in agreement with previous data in rats and humans
(6, 7, 19). However, AQP4
deletion was not associated with changes in gastric mucosal morphology at the light microscopy level or in the rates of basal or stimulated acid or fluid secretion. Furthermore, AQP4 deletion did not affect the
ability of the stomach to generate a highly acidic pH, nor did it
affect fasting serum gastrin concentrations. Together these data
provide direct evidence against a role for AQP4 in gastric acid production.
Various transgenic mouse strains have shown altered gastric acid
secretory capabilities. Mice lacking the gastrin/CCK-B receptor exhibit
markedly impaired acid secretion, as well as a tenfold elevated serum
gastrin level, indicating a critical role for gastrin in the
stimulation of acid secretion (14, 27,
31). Gastrin-deficient mice exhibit no demonstrable
stimulated acid secretory response to histamine, carbachol, or gastrin
(8). AQP4 /
mice show no demonstrable impairment in
gastric acid secretion, nor do they exhibit elevated serum gastrin
concentrations. Although strong agonist-stimulated gastric acid
secretion was found, the rates of secretion in our study were somewhat
lower than those reported in some rodent studies and comparable to
others. In Urethane- or ketamine plus xylaxine-anesthetized +/+ mice,
basal acid output ranges between 0.1 and 6 µeq/10 min
(8, 10, 18). The lower secretion
rates found here may in part be due to the suppressive effect of the
intraperitoneal pentobarbital that was administered during the several
hours needed to complete each experiment. Pentobarbital is reported to
have an inhibitory effect on gastric acid secretion (1,
26). However, because of the substantial
agonist-stimulated acid secretion and the high sensitivity of the
methods used here, we believe that it is unlikely that subtle defects
in gastric acidification in AQP4
/
mice were missed.
It has been proposed that parietal cells function differently throughout their lifespan (12, 13). Parietal stem cells reside in the neck of the gastric pit. As parietal cells mature, they migrate downward toward the base of the pit. It has been suggested that mouse parietal cells secrete acid in the early phase of their lives on the basis of electron microscopy and [3H]thymidine radioautographic analyses (12, 13). As they mature toward the base of the pit, parietal cells secrete less acid and more water. Our colocalization studies of AQP4 and H+-K+-ATPase are consistent with this theory of dual functionality of the parietal cell during its lifespan. The presence of AQP4 only in the base of the gastric pits suggests a greater role in water transport by these parietal cells compared with the more superficial parietal cells in a pit.
AQP4 has been implicated in water transport in several organ systems
including kidney, brain, and lung (4, 16,
17, 25, 29). In the stomach,
parietal cells account for only a small fraction of the total
epithelial surface area and AQP4 is expressed in only a fraction of
parietal cells. Although acid secretion is concurrent with water
secretion under stimulated conditions, the relative contribution of
fluid secretion from parietal cells is unknown. Our measurement of
total gastric Jw was probably not sensitive
enough to determine whether a defect in fluid transport exists in the
parietal cells of /
mice. It is possible that such a defect might
be detected if fluid transport studies are done on isolated, perfused
gastric pits. In any case, it is unlikely that AQP4 plays an important
physiological role in total gastric fluid secretion in this regard.
Although our results provide functional evidence against a role for
AQP4 in gastric acid production and fluid secretion, they do not
address the issue of why AQP4 is strongly expressed at the basolateral
membrane in gastric parietal cells. AQP4 may increase basolateral
membrane water permeability so as to maintain constant parietal cell
volume under conditions where the apical cell surface is exposed to
fluids of very different osmolalities. However, the AQP4 /
mice
have apparently normal gastric wall morphology and nutritional status.
AQP4 expression in gastric parietal cells may represent a vestigial
remnant of an earlier time in which high parietal cell water
permeability was required. Our results here underscore the notion that
the tissue-specific expression of an aquaporin protein does not ensure
physiological significance. A similar conclusion was reached in several
recent examples, including AQP4 in skeletal muscle (35),
AQP1 and AQP4 in salivary gland (15), and several
aquaporins including AQP4 in lacrimal gland (20), where
aquaporin deletion was not associated with demonstrable phenotypic abnormalities.
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ACKNOWLEDGEMENTS |
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We thank Liman Qian for mouse breeding and genotypic analysis and Dr. Gary M. Gray for helpful advice and discussions.
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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-35124 and DK-43840, National Heart, Lung, and Blood Institute Grants HL-59198 and HL-60288, National Cystic Fibrosis Foundation Grant R613 (A. S. Verkman), and a grant from the Society for Surgery of the Alimentary Tract Career Development (J. A. Bastidas).
Address for reprint requests and other correspondence: J. A. Bastidas, Dept. of Surgery, Stanford Univ. School of Medicine, Rm. H3680, Stanford, CA 94305-5655 (E-mail: jaba{at}stanford.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 15 November 1999; accepted in final form 22 March 2000.
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