1 Department of Medicine and 5 Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Florida 32610; 3 Department of Physiology, School of Medicine, Dongguk University, Kyungju, 780-714; 4 Department of Anatomy, College of Medicine, Catholic University, Seoul 137-701, Korea; and 2 The Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus C, Denmark
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ABSTRACT |
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Recent studies have demonstrated that a
novel anion exchanger, pendrin, is expressed in the apical domain of
type B intercalated cells in the mammalian collecting duct. The purpose
of this study was 1) to determine the expression and
distribution of pendrin along the collecting duct and connecting tubule
of mouse and rat kidney and establish whether pendrin is expressed in
the non-A-non-B intercalated cells and 2) to determine the
intracellular localization of pendrin in the different populations of
intercalated cells by immunoelectron microscopy. A peptide-derived
affinity-purified antibody was generated that specifically recognized
pendrin in immunoblots of rat and mouse kidney. Immunohistochemistry
and confocal laser scanning microscopy demonstrated the presence of pendrin in apical domains of all type B intercalated cells in mouse and
rat connecting tubule and collecting duct. In addition, strong pendrin
immunostaining was observed in non-A-non-B intercalated cells. There
was no labeling of type A intercalated cells. Immunoelectron microscopy
demonstrated that pendrin was located in the apical plasma membrane and
intracellular vesicles of both type B intercalated cells and
non-A-non-B cells; the latter was identified by the presence of
H+-ATPase in the apical plasma membrane. The results of
this study demonstrate that both pendrin and H+-ATPase are
expressed in the apical plasma membrane of non-A-non-B intercalated
cells, suggesting that these cells are capable of both
HCO
acid-base metabolism; connecting tubule; collecting duct; bicarbonate secretion
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INTRODUCTION |
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THE COLLECTING DUCT
PLAYS an important role in urine acidification. Acid secretion
occurs along the entire collecting duct (2), and the
cortical collecting duct (CCD) is capable of both proton and
HCO
At least two types of intercalated cells, type A and type B, are
present in the CCD and the connecting tubule (CNT) of rats (1, 5,
13, 36), mice (12, 31), and rabbits (23, 24,
38, 39). Type A intercalated cells secrete protons mediated by a
vacuolar type H+-ATPase, which is located in the apical
plasma membrane and apical tubulovesicles (5, 12, 24, 31,
35). They reabsorb HCO/HCO
Type B intercalated cells secrete HCO/HCO
/HCO
Despite intensive research, the protein responsible for apical
Cl/HCO
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METHODS |
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Membrane fractionation for immunoblotting. Kidneys from normal male Munich-Wistar rats were divided into three zones: cortex/outer stripe of the outer medulla, inner stripe of the outer medulla, and inner medulla. Kidneys from normal NMRI mice were divided into two parts only: cortex/outer medulla and inner medulla. The tissues were homogenized (0.3 M sucrose, 25 mM imidazole, 1 mM EDTA, pH 7.2, containing 8.5 µM leupeptin, 1 mM phenylmethyl sulfonylfluoride) with an Ultra-Turrax T8 homogenizer (IKA Labortechnik) at maximum speed for 30 s, and the homogenates were centrifuged in an Eppendorf centrifuge at 4,000 g for 15 min at 4°C to remove whole cells, nuclei, and mitochondria. The supernatant was then centrifuged at 200,000 g for 1 h to produce a pellet containing membrane fractions enriched for both plasma membranes and intracellular vesicles. The samples were prepared for gel electrophoresis by adding Laemmli sample buffer containing 2% SDS (final concentration) to the resuspended pellets.
Deglycosylation of membrane proteins. Twenty micrograms of membrane proteins from whole rat kidney, prepared as described above, were denatured by heating to 100°C in 1% SDS for 5 min, diluted 1:9 with 1% Triton X-100 in the buffer described above (without leupeptin and phenylmethyl sulfonylfluoride), and incubated with 4 U of N-glycosidase (PNGase F, Boehringer Mannheim, Mannheim, Germany) overnight at room temperature (RT). The incubation was stopped by addition of Laemmli buffer.
Antibodies.
To identify pendrin in the kidney, polyclonal antibodies were generated
against synthetic peptides corresponding to 22 amino acids,
MEAEMNAEELDVQDEAMRRLAS, of the COOH terminus of mouse pendrin conjugated to keyhole limpet hemocyanine. Immune sera against the
erythrocyte Cl/HCO
Electrophoresis and immunoblotting. Samples of membranes from rat and mouse kidney (see Membrane fractionation for immunoblotting for details) were run on 9% polyacrylamide minigels (Mini Protean II, Bio-Rad). After transfer by electroelution to nitrocellulose membranes, blots were blocked with 5% milk in PBS-T (80 mM Na2HPO4, 20 mM NaH2PO4, 100 mM NaCl, 0.1% Tween 20, pH 7.5) for 1 h and incubated overnight at 4°C with anti-pendrin antibodies. The labeling was visualized with horseradish peroxidase (HRP)-conjugated secondary antibodies (diluted 1:3,000; P448, DAKO, Glostrup, Denmark) by using an enhanced chemiluminescence system (Amersham International). Immunoblotting was used to test the specificity of the affinity-purified anti-pendrin antibodies by applying the immunonizing peptides on 12% polyacrylamide gels, which were subsequently processed as described above. Immunolabeling controls were performed using preabsorption of the immune serum with the immunizing peptide for 2 h at RT.
Immunohistochemistry. Male Sprague-Dawley rats and C57BL/6 mice were used. The animals were anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt). The kidneys were initially perfused briefly through the abdominal aorta or through the left ventricle with PBS to rinse away all blood. This was followed by perfusion with a periodate-lysine-paraformaldehyde for 10 min. The kidneys were removed and cut into 1- to 2-mm-thick slices that were fixed additionally by immersion in the same fixative for 2 h at RT and then overnight at 4°C. Sections of tissue were cut transversely through the entire kidney on a Vibratome (Pelco 101, sectioning series 1000, Ted Pella, Redding, CA) at a thickness of 50 µm and processed for immunohistochemical studies by using an HRP preembedding technique. To identify the intercalated cell populations that express pendrin, a multiple labeling procedure was used. AE1 and pendrin were labeled simultaneously by a double-labeling technique using a preembedding method, which was followed by labeling for H+-ATPase using a postembedding method.
Preembedding method for AE1 and pendrin or AE1 alone. Sections of periodate-lysine-paraformaldehyde-fixed tissue were cut transversely through the kidney on a Vibratome at a thickness of 50 µm and processed for immunohistochemistry by using an indirect immunoperoxidase method. All sections were washed with 50 mM NH4Cl in PBS three times for 15 min. Before incubation with the primary antibodies, the tissue sections were incubated for 3 h with PBS containing 1% bovine serum albumin, 0.05% saponin, and 0.2% gelatin (solution A). The sections were then incubated overnight at 4°C either in a mixture of antisera against AE1 (1:2,000) and pendrin (1:3,000) or with the antibody against AE1 (1:2,000) alone in PBS containing 1% bovine serum albumin (solution B). After several washes with solution A, the tissue sections were incubated for 2 h in HRP-conjugated donkey anti-rabbit IgG, Fab fragment (Jackson ImmunoResearch Laboratories), diluted 1:100 in solution B. The tissues were then rinsed, first in solution A and subsequently in 0.05 M Tris buffer, pH 7.6. For the detection of HRP, the sections were incubated in 0.1% 3,3'-diaminobenzidine in 0.05 M Tris buffer for 5 min, after which H2O2 was added to a final concentration of 0.01% and the incubation was continued for 10 min. After washing with Tyrode buffer three times, the sections were dehydrated in a graded series of ethanol and propylene oxide and embedded in TAAB812 between polyethylene vinyl sheets.
Postembedding method for H+-ATPase, pendrin, or AQP2. From the flat-embedded 50-µm-thick sections processed for double immunolabeling of pendrin and AE1 or AE1 alone, sections from the renal cortex were excised and glued onto empty blocks of TAAB812, and consecutive 1.5-µm sections were cut for postembedding immunolabeling. The sections were treated for 15 min with a saturated solution of sodium hydroxide in absolute ethanol to remove the resin. After three brief rinses in absolute ethanol, the sections were hydrated with graded ethanol and rinsed in tap water. The sections were rinsed with PBS, incubated in normal donkey serum for 1 h, and subsequently incubated overnight with antibody against H+-ATPase (1:2,000), pendrin (1:3,000), or AQP2 (1:1,000) at 4°C. The sections were rinsed with PBS and incubated for 2 h in HRP-conjugated donkey anti-rabbit IgG, Fab fragment, and washed again with PBS. For detection of antibodies, Vector SG (Vector Laboratories) was used as the chromogen to produce a gray-blue label, which is easily distinguished from the brown label produced by 3,3'-diaminobenzidine in the first immunolocalization procedure for pendrin and AE1 by the preembedding method. The sections were washed with distilled water, dehydrated with graded ethanol and xylene, mounted in Canada balsam, and examined by light microscopy.
Confocal laser scanning microscopy and immunoelectron microscopy. Kidneys from Munich-Wistar rats and NMRI mice were fixed by retrograde perfusion via the aorta with 4% paraformaldehyde, in 0.1 M cacodylate buffer, pH 7.4, as previously described (9). For immunofluorescence microscopy, kidney blocks containing all kidney zones were dehydrated and embedded in paraffin. The paraffin-embedded tissues were cut at 2 µm on a rotary microtome (Leica, Heidelberg, Germany). The sections were dewaxed and rehydrated. To reveal antigens, sections were placed in 1 mM Tris buffer (pH 9.0) supplemented with 0.5 mM EGTA and were heated by a microwave oven for 10 min. Nonspecific binding of Ig was prevented by incubating the sections in 50 mM NH4Cl for 30 min followed by blocking in PBS supplemented with 1% BSA, 0.05% saponin, and 0.2% gelatin. Sections were incubated overnight at 4°C with pendrin antibodies. In double-labeled fluorescence studies, the vacuolar H+-ATPase was localized with mouse monoclonal antibodies that were mixed with the antibody against pendrin. The labeling was visualized by using a rhodamine-conjugated goat anti-mouse antibody (diluted 1:200; Alexa 546, Molecular Probes) mixed with a fluorescein-conjugated goat anti-rabbit antibody (diluted 1:200; Alexa 488, Molecular Probes). The microscopy was carried out by using an SP2 laser confocal microscope (Leica).
For immunoelectron microscopy, the frozen samples were freeze substituted in a Reichert AFS freeze substitution unit (9, 15). In brief, the samples were sequentially equilibrated over 3 days in methanol containing 0.5% uranyl acetate at temperatures gradually raised from ![]() |
RESULTS |
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Immunoblotting of pendrin in rat and mouse kidney membrane.
To establish the presence and examine the cellular distribution of
pendrin in the kidney, a rabbit antibody raised against a peptide
corresponding to mouse pendrin was produced. The antibody recognized
the peptide on immunoblots (not shown) and specifically recognized a
~126-kDa band on immunoblots using membrane fractions from mouse and
rat kidney (Fig. 1). Labeling was
observed in membrane fractions from the rat cortex/outer stripe
of the outer medulla but not in the inner stripe of the outer medulla
or the inner medulla (Fig. 1A). A band of the same size was
also seen in immunoblots of membrane fractions from mouse kidney
cortex/outer medulla, but no band was detected in membranes from the
inner medulla (Fig. 1A). The specificity of the labeling was
confirmed by using anti-pendrin antibody preabsorbed with the
immunizing peptide (Fig. 1B). The size of the recognized
protein is larger than the predicted size of ~87 kDa, suggesting that
pendrin is glycosylated or posttranslationally modified in other ways.
Consistent with this, immunoblotting using membrane fractions subjected
to deglycosylation by N-glycosidase (PNGase F) treatment
revealed a marked reduction in molecular mass corresponding to ~95
kDa (Fig. 1C), which is closer to the predicted molecular
size of pendrin.
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Cellular and subcellular localization of pendrin in mouse kidney
determined by double- and triple-labeling immunocytochemistry and
confocal laser microscopy.
To evaluate the overall distribution of pendrin in mouse kidney,
immunohistochemistry was performed by using paraffin sections or
preembedding immunostaining of 50-µm-thick vibratome sections. Immunohistochemistry revealed abundant labeling of the CNT and CCD in
the outer and inner cortex (inset, Fig.
2A). Confocal laser scanning microscopy revealed strong apical pendrin immunoreactivity (green, Fig. 2A) in type B intercalated cells with
basolateral H+-ATPase (red, Fig. 2A). In
contrast, no labeling was observed in type A intercalated cells. As
shown in Fig. 2, B-D, pendrin immunolabeling was
observed in a minority of intercalated cells expressing apical
H+-ATPase (arrows, Fig. 2), strongly suggesting that
pendrin is expressed in non-A-non-B cells. To confirm this and identify
the three subtypes of intercalated cells with certainty, the
distribution of pendrin was determined in 50-µm-thick vibratome
sections processed for preembedding immunostaining, followed by
sectioning and postembedding double labeling (see METHODS).
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Immunoelectron microscopic localization of pendrin in mouse kidney.
Immunoelectron microscopy was conducted by using immunogold labeling of
sections prepared from mouse kidney embedded in Lowicryl HM20 by
cryosubstitution. In sections from the CNT, abundant immunogold labeling was associated with apical plasma membrane domains (arrows, Fig. 4A) as well as subapical
intracellular vesicles of non-A-non-B intercalated cells (Fig. 4,
A and B), which is consistent with the results of
immunoperoxidase and immunofluoresence microscopy. There was no
labeling of the basolateral plasma membrane of non-A-non-B intercalated
cells (Fig. 4C). Immunolabeling controls using antibody preabsorbed with excess immunizing peptide produced no labeling (not
shown). Type A intercalated cells, which are characterized by prominent
microplicae and abundant subapical tubulovesicular structures (Fig.
5, A and B) or CNT
cells (not shown), exhibited no immunogold labeling of pendrin, which
is consistent with immunoperoxidase and immunofluorescence microscopic
observation. In the CCD, strong immunogold labeling was observed in the
apical plasma membrane and apical intracellular vesicles of type B
intercalated cells (not shown) as well as non-A-non-B intercalated
cells (Fig. 6B). There was no
labeling of the basolateral plasma membrane (not shown). The
identity of the cells was confirmed by H+-ATPase labeling
of the same cells in serial sections (Fig. 6, E-G).
There was no pendrin immunolabeling in principal cells (Fig. 6C) or type A intercalated cells (Fig. 6D).
Immunolabeling controls using antibody preabsorbed with excess
immunizing peptide produced no labeling (not shown).
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Cellular and subcellular localization of pendrin in rat kidney
determined by double- and triple-labeling immunocytochemistry, confocal
laser microscopy, and immunoelectron microscopy.
The distribution of pendrin in rat kidney was determined in paraffin
sections and in 50-µm-thick vibratome sections processed for
immunolabeling. At low magnification, pendrin immunolabeling was
observed in the CNT and CCD (inset, Fig.
7A), consistent with results
from previous studies (21). Confocal laser
scanning microscopy revealed strong apical immunostaining for pendrin
in type B intercalated cells (green, Fig. 7A), which were
identified by basolateral H+-ATPase labeling (red, Fig.
7A). There was no labeling in intercalated cells with apical
H+-ATPase in the rat CCD (Fig. 7A). In the CNT
(Fig. 7, B-D), pendrin and H+-ATPase were
colocalized in the apical region of a minority of intercalated cells
(arrows, Fig. 7D), suggesting that pendrin was expressed in
non-A-non-B intercalated cells. To establish this interpretation, the
distribution of pendrin was determined by triple immunolabeling in
50-µm-thick vibratome sections processed for preembedding
immunolabeling, followed by sectioning and postembedding labeling (see
METHODS) or by immunoelectron microscopy. The triple labeling for pendrin, AE1, and H+-ATPase demonstrated that
apical pendrin labeling was seen in AE1-negative intercalated cells
corresponding to type B intercalated cells with basolateral
H+-ATPase in the CCD (*, Fig.
8A) and CNT as well as in
non-A-non-B intercalated cells with apical H+-ATPase (not
shown). In contrast, AE1-positive cells were associated with apical
H+-ATPase labeling, corresponding to type A intercalated
cells (arrows, Fig. 8A). Immunoelectron microscopy confirmed
the presence of strong labeling of the apical plasma membrane and
apical intracellular vesicles of type B intercalated cells (Fig.
9) and non-A-non-B intercalated cells,
identified by apical H+-ATPase labeling (not shown),
whereas no labeling was seen in the basolateral plasma membrane.
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DISCUSSION |
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The results of the present study demonstrate that pendrin is
expressed in the apical domain of all type B intercalated cells as well
as in non-A-non-B intercalated cells in the CNT and CCD of both mouse
and rat kidney. The demonstration that pendrin is expressed in type B
intercalated cells is in agreement with observations by Royaux et al.
(21) and provide further support for pendrin representing
the apical anion exchanger of type B intercalated cells as indicated by
their elegant transport studies in isolated CCD segments from
pendrin-deficient mice (21). The results of our
immunoelectron microscopic studies revealed strong labeling for pendrin
in the apical plasma membrane as well as in apical intracellular
vesicles of both type B and non-A-non-B intercalated cells. As reported
previously (21), there was no expression of pendrin in the
AE1-positive type A intercalated cells. Taken together, these
observations indicate that both type B and non-A-non-B intercalated
cells are capable of pendrin-mediated HCO
Pendrin is a novel anion exchanger that is closely related to a family
of sulfate transporters. Mutations in the gene that encodes pendrin are
known to cause pendred syndrome, a genetic disorder associated with
goiter and deafness (7). Previous studies have
demonstrated strong expression of pendrin in both the thyroid gland
(20) and the inner ear (8), and there is evidence from studies in Xenopus laevis oocytes that pendrin
functions as an iodide transporter (28) and a
chloride/formate exchanger (27). In addition, Soleimani et
al. (29) have provided evidence that pendrin expressed in
human embryonic kidney HEK-293 cells can function as a
Cl/OH
or a
Cl
/HCO
Recently it was reported that pendrin mRNA (29) and
protein (21) are expressed in the kidney.
Immunofluorescence studies by Royaux et al. (21)
demonstrated strong expression of pendrin in the apical domain of
AE1-negative intercalated cells, presumably type B intercalated cells,
in the CCD and CNT of rat, mouse, and human kidney. It is generally
accepted that type B intercalated cells are involved in
HCO/HCO
/HCO
Soleimani et al. (29) have examined the expression of pendrin in microdissected tubule segments by using RT-PCR and found that pendrin mRNA was present in both the proximal tubules and the CCD. In contrast, there was no evidence of pendrin immunoreactivity in the proximal tubule in the present study or in the study by Royaux et al. (21). The reason for this discrepancy is not known. However, it is possible that the primers used for PCR reacted with the cDNA for another member of the same anion exchanger family to which pendrin belongs. In this regard, it is of interest that a recent study by Knauf et al. (14) identified a homolog of pendrin, a chloride/formate exchanger, in the brush-border membrane of the mouse proximal tubule. It should be pointed out that recent studies have reported the expression of a second anion exchanger, AE4, in the apical region of type B intercalated cells in rabbits (33). Whether this transporter is also expressed in mouse and rat kidney remains to be established.
The non-A-non-B intercalated cell was first described in rat kidney by Kim et al. (13) and Madsen et al. (16), who reported that a few intercalated cells in the CNT exhibited ultrastructural characteristics that were distinct from those of type A and type B intercalated cells. The non-A-non-B intercalated cells are larger than type A and type B intercalated cells; they are rich in mitochondria and have numerous apical microprojections similar to those described in type A intercalated cells. It was suggested that they might correspond to the AE1-negative intercalated cells with apical H+-ATPase that according to a previous study by Alper et al. (1), constituted ~1% of the intercalated cells in the renal cortex of rats. Subsequent studies revealed that non-A-non-B cells were also present in mice and confirmed that these cells exhibit strong labeling for H+-ATPase in the apical plasma membrane but do not express AE1 (12, 31). Moreover, the prevalence of the non-A-non-B intercalated cells in the CNT and CCD was found to be higher than previously anticipated, and it was demonstrated that the majority of intercalated cells in the CNT of the mouse belongs to the non-A-non-B subtype (12).
The function of the non-A-non-B intercalated cells remains to be
established. It is not known whether they represent a distinct subtype
of intercalated cell or a modified form of either the type A or the
type B intercalated cell. Moreover, the response of the non-A-non-B
intercalated cells to changes in acid-base balance has not been
investigated in detail, and there are no studies of acid-base transport
in the CNT of mice, in which non-A-non-B cells constitute a major
proportion of the cells. However, the demonstration that these cells
express both H+-ATPase and the anion exchanger pendrin in
the apical plasma membrane suggests that the non-A-non-B intercalated
cell represents a unique cell type capable of both apical proton
secretion and apical HCO
It has been suggested that the non-A-non-B cell might represent a modified type B intercalated cell. Brown and Breton (4) have proposed that the cellular location of H+-ATPase in type B intercalated cells can be apical, basolateral, bipolar, or diffuse. In that case, all AE1-negative intercalated cells, including non-A-non-B cells, would be classified as type B intercalated cells. Whether the classification proposed by Brown and Breton is correct remains to be established. However, future studies of the response of the non-A-non-B intercalated cells to chronic acid-base disturbancies might help elucidate this question.
It has been previously suggested that intercalated cells might be able to change their polarity depending on the acid-base status of the animal (25). Consistent with this, a recent study demonstrated an adaptive remodeling of type B intercalated cells to functionally resemble type A intercalated cells from the CCD of rabbit kidney in response to acid incubation, and this process was associated with deposition of the hensin in the extracellular matrix of these cells (26). However, the percentage of intercalated cells with basolateral AE1 immunoreactivity appears to be constant during various experimental conditions (11, 22), and AE1 has never been observed in the apical plasma membrane of any cells in the collecting duct in vivo. Thus experimental evidence that intercalated cells can change their polarity in vivo is lacking. However, it should be pointed out that a recent study by Bagnis et al. (3) has reported striking changes in the prevalence of the different cell populations in the collecting duct after treatment with the carbonic anhydrase inhibitor acetazolamide. Rats treated with acetazolamide for 2 wk showed a significant increase in the percentage of type A intercalated cells in both the CCD and the outer medullary collecting duct. This was associated with a decrease in the percentages of type B intercalated cells and principal cells in the CCD and outer medullary collecting duct, respectively. Whether the reduction in the prevalence of type B intercalated cells and principal cells represents a remodeling or an elimination of the cells remains to be established.
The results of this study demonstrate that pendrin is expressed in the
apical plasma membrane and apical intracellular vesicles of both type B
and non-A-non-B intercalated cells. Moreover, non-A-non-B intercalated
cells share features of both type A and type B intercalated cells,
expressing apical pendrin similar to type B intercalated cells and
apical H+-ATPase similar to type A intercalated
cells. On the basis of these characteristics, we suggest that
non-A-non-B intercalated cells represent a separate cell type with
unique transport properties. Furthermore, on the basis of the
observation that pendrin is located in both the apical plasma membrane
and the apical intracellular vesicles, we propose that
HCO
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ACKNOWLEDGEMENTS |
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The authors thank Helle Høyer, Zhila Nikrozi, Inger Merete Paulsen, Mette Vistisen, Merete Pedersen, and Gitte Christensen for technical assistance.
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FOOTNOTES |
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The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). Support for this study was provided by the Karen Elise Jensen Foundation, Human Frontier Science Program, European Commission (KA 3.1.2 and KA 3.1.3), Novo Nordic Foundation, Danish Medical Research Council, University of Aarhus Research Foundation, University of Aarhus, and Dongguk University.
Address for reprint requests and other correspondence: S. Nielsen, The Water and Salt Research Ctr., Institute of Anatomy, Univ. of Aarhus, DK-8000 Aarhus C, Denmark (E-mail: sn{at}ana.au.dk).
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.
May 22, 2002;10.1152/ajprenal.00037.2002
Received 28 January 2002; accepted in final form 8 May 2002.
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