1 Department of Medicine, University of Cincinnati, and 2 Veterans Affairs Medical Center at Cincinnati, Cincinnati, Ohio 45267-0485
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ABSTRACT |
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Pendrin is an apical
Cl/OH
/HCO
-intercalated cells (
-ICs) of rat and mouse cortical collecting
duct (CCD). However, little is known about its regulation in acid-base
disorders. Here, we examined the regulation of pendrin in metabolic
acidosis, a condition known to decrease HCO
/HCO
-ICs
was determined as amplitude and rate of intracellular pH change when Cl
was removed in isolated, microperfused CCDs. Intracellular pH was
measured by single-cell digital ratiometric imaging using fluorescent
pH-sensitive dye
2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein-AM. Pendrin mRNA expression in kidney cortex was examined by Northern blot
hybridizations. Expression of pendrin protein was assessed by indirect
immunofluorescence. Microperfused CCDs isolated from acidotic rats
demonstrated ~60% reduction in apical
Cl
/HCO
-ICs
(P < 0.001 vs. control). Northern blot hybridizations
indicated that the mRNA expression of pendrin in kidney cortex
decreased by 68% in acidotic animals (P < 0.02 vs.
control). Immunofluorescence labeling demonstrated significant
reduction in pendrin expression in CCDs of acidotic rats. We conclude
that metabolic acidosis decreases the activity of the apical
Cl
/HCO
-ICs of the rat CCD by reducing the expression of pendrin. Adaptive downregulation of
pendrin in metabolic acidosis indicates the important role of this
exchanger in acid-base regulation in the CCD.
kidney; intercalated cells
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INTRODUCTION |
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ONE-THIRD OF THE KIDNEY
CORTICAL collecting duct (CCD) cell population comprises
intercalated cells, which are responsible for the final adjustments of
acid-base balance (31). In response to acid or alkali
loading, CCD reabsorbs or secretes more HCO-intercalated cells (
-ICs), which are modeled to secrete acid through an apical
H+-ATPase and basolateral
Cl
/HCO
-intercalated cells (
-ICs), which are modeled to secrete HCO
/HCO
/HCO
-ICs as anion exchanger 1 (AE1) (reviewed in Ref.
31). However, the molecular identity of the apical
Cl
/HCO
-ICs has long
remained unknown.
Recent molecular studies have identified a large, highly conserved
family of membrane proteins (designated as SLC26A), many of which have
been shown to transport anions. Three closely related members of this
family are downregulated in adenoma (DRA or SLC26A3), pendrin (PDS or
SLC26A4), and PAT1 (CFEX or SLC26A6) (14, 17, 19, 20, 44).
All three transporters mediate Cl/HCO
/HCO
-ICs of CCD
(28, 35, 36).
Metabolic acidosis decreases the apical
Cl/HCO
-ICs (25, 30, 32, 33, 40). However, little is known
about the regulation of the apical
Cl
/HCO
-ICs of either control or acidotic rats. Furthermore, no study has examined the molecular adaptation of
-IC apical
Cl
/HCO
/HCO
-ICs in rats subjected to acid loading.
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METHODS |
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Animals.
Metabolic acidosis was generated according to established protocols
(1, 9). Female Sprague-Dawley rats, 100-150 g, were given 280 mM NH4Cl in their drinking water for 4 days.
Serum HCO
Isolation of CCDs and in vitro microperfusion.
Rats were killed by intraperitoneal injection of pentobarbital sodium
(100 mg/kg of body wt). Kidneys were quickly removed and placed in
ice-cold dissection medium (solution 1; Table
1). Thin coronal slices (~1 mm) were
cut and transferred to the dissection chamber. CCDs were obtained by
freehand dissection. Dissected tubules were quickly transferred to the
1.5-ml temperature-controlled specimen chamber mounted on an inverted
Zeiss Axiovert S-100 microscope (Carl Zeiss, Thornwood, NY). Tubules
were perfused by using concentric glass pipettes according to the
method of Burg and colleagues (7, 8) with modifications
(40) at 5-cm water pressure. Solutions used to perfuse and
bath the tubules are listed in Table 1. Solutions were delivered to the
specimen chamber in tubing impermeable to CO2 and
O2 (Cole Palmer, Chicago, IL) by a peristaltic pump
(Peristar, WPI, Sarasota, FL) at a rate of 1 ml/min. Fluid in the
chamber was constantly superfused with 95% O2-5%
CO2 to minimize gas loss and help keep the pH of the bath
fluid constant. Chamber pH was frequently checked on a pH meter (model
B213, Horiba). Initially, tubules were perfused with fast green dye
(Sigma, St. Louis, MO) to identify the damaged cells, because damaged
cells take up the dye. Tubules were carefully inspected and discarded if damaged cells were found (41).
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Intracellular pH measurement in intercalated cells. After 15-20 min equilibration in solution 2, the tubule was perfused with 5 µM 2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein AM (BCPCF-AM) for 5 min. Only intercalated, but not principal, cells take up the pH-sensitive dye when perfused from the luminal side (45). BCPCF-AM is a close analog of BCECF-AM, with improved spectral characteristics (a higher absorption at isosbestic point yields a better signal-to-noise ratio) (16). In our preliminary experiments, we noticed that BCPCF-AM was better retained in rat intercalated cells. Fluorescent measurements were done with the Zeiss Axiovert S-100 inverted microscope equipped with Attofluor RatioVision digital imaging system (Attofluor, Rockville, MD). An Achroplan ×40/0.8 water objective with 3.6-mm working distance was used. Excitation wavelengths were recorded at 488 and 440 nm, and emission was measured at 520 nm. Attofluor RatioVision software allowed for "regions of interest" to be applied to individual cells so that multiple cells in a single tubule were simultaneously examined. Generally, three to seven cells were examined per tubule. Only one tubule per animal was examined. Digitized images were analyzed by using Attograph software (Attofluor). Intracellular calibration was performed by using the high-K+-nigericin method (24, 30, 33, 37, 45). A three-point calibration curve was used to convert the recorded ratios into intracellular pH (pHi) values. pH clamp calibration values (7.5, 7.0, and 6.5) were recorded from each cell that was selected for experimental measurements in every tubule at the end of the experiment.
Apical ClRNA isolation and Northern blot hybridization.
Total cellular RNA was extracted from cortex by the method of
Chomczynski and Sacchi (10), quantitated
spectrophotometrically, and stored at 80°C. Total RNA samples (30 µg/lane) were fractionated on a 1.2% agarose-formaldehyde gel and
transferred to Magna NT nylon membranes (MSI). Membranes were
cross-linked by ultraviolet light and baked for 1 h. Hybridization
was performed according to Church and Gilbert (11). A
pendrin-specific cDNA probe (36) was labeled with
[32P]deoxynucleotides by using the Rad-Prime DNA labeling
kit (GIBCO-BRL). The membranes were washed, blotted dry, exposed to a
PhosphorImager cassette at room temperature for 24-72 h, and read
by the PhosphorImager (Molecular Dynamics, Sunnyvale, CA).
Nephron segment RT-PCR. CCDs were dissected as single-nephron segments from freshly killed normal or acidotic rat kidneys at 4-6°C as described (36). The dissection media comprises 140 mM NaCl, 2.5 mM K2HPO4, 2 mM CaCl2, 1.2 mM MgSO4, 5.5 mM D-glucose, 1 mM Na citrate, 4 mM Na lactate, and 6 mM L-alanine, pH 7.4, and bubbled with 100% O2. Tubule lengths were ~0.5-0.7 mm for both control and acidotic animals. For each RT-PCR, two nephron segments (CCDs) from each rat were pooled in a small volume (5-10 µl) of ice-cold PBS. The tubules were centrifuged at 12,000 g for 1 min at room temperature, and the PBS was removed and replaced with 10 µl of a tubule lysis solution consisting of 0.9% Triton X-100, 5 mM DTT, and 1 U/µl rRNasin (Promega). After 5 min on ice, the tubules were gently agitated by tapping the tube, and 1 µl (0.5 µg) oligo(dT) primer, 1 µl H2O, 4 µl 5× reverse transcription buffer, 2 µl DTT (0.1 M), and 1 µl dNTPs (10 mM each) were added. The reaction was equilibrated to 42°C for 2 min, and 1 µl SuperScript II RT (Life Technologies) was added, mixed, and incubated for 1 h at 42°C. After reverse transcription, 30 µl of TE (10 mM Tris · Cl and 1 mM EDTA, pH 8.0) were added, and the combined mixture was heated to 95°C for 5 min and placed on ice.
The following oligonucleotide primers (5'-CAT TCT GGG GCT GGA CCT C and 5'-CCT TCG GGA CAT TCA CTT TCA C) were designed on the basis of rat pendrin cDNA (GenBank accession no. AF-167412) and used for nephron segment RT-PCR. These primers should amplify a PCR fragment of 488 bp. Amplification of the pendrin cDNA by the PCR was performed by using parameters previously established with rat CCD (36). Briefly, each PCR contained 10 µl cDNA, 5 µl 10× PCR buffer (with 20 mM MgCl2), 1 µl 10 mM dNTPs, 10 pmol/primer, and 2.5 µl Taq DNA polymerase in a final volume of 50 µl. Cycling parameters were 95°C for 45 s, 47°C for 45 s, and 72°C for 2 min. The expression ofImmunocytochemistry: antibodies. For pendrin, polyclonal antibodies were raised in two rabbits against a synthetic peptide corresponding to amino acids 734-752 (CKSREGQDSLLETVARIRDC). The sequence of the synthetic peptide used for antibody generation was identical for rat, mouse, and human pendrin. Antibodies were purified with cystein-affinity columns. This antibody is highly specific and labels the apical membranes of a subset of CCD cells (35).
For aquaporin 2 (AQP2), peptide-derived polyclonal antibodies specific to the AQP2 water channel were raised in our laboratory as described (2). The rat AQP2 peptide has the following sequence: NH2-CEVRRRQSVELHSPQSLPRG- SKA-COOH, which corresponds to amino acid residues 250-271 of the COOH-terminal tail of the vasopressin-regulated AQP2 water channel. This antibody is highly specific and has been successfully used to examine the regulation of AQP2 in pathophysiological disorders (2).Immunofluorescense. Animals were killed with an overdose of pentobarbital sodium and perfused through the left ventricle of the heart with 200 ml of 0.9% saline followed by cold 500 ml of 4% paraformaldehyde in 0.1 M sodium-phosphate buffer (pH 7.4). Kidneys were removed, cut in tissue blocks, and left in the same fixative solution overnight at 4°C.
For cryosections, tissue blocks were removed from the fixative solution and soaked in 30% sucrose overnight. The tissue was frozen on dry ice, and 5-µm sections were cut with a cryostat and stored atMaterials. [32P]dCTP was purchased from New England Nuclear (Boston, MA). The RadPrime DNA labeling kit was purchased from GIBCO-BRL. BCECF-AM and BCPCF-AM were from Molecular Probes. Nitrocellulose filters and and all other chemicals were purchased from Sigma. Nigericin was dissolved in ethanol as 10 mM stock and diluted 1:1,000 for the final concentration of 10 µM.
Statistics.
Results are expressed as means ± SE. Statistical significance
between experimental groups was determined by Student's
t-test, as required. Significance was asserted if
P < 0.05. Comparison of the number of intercalated
cell types in control and acidotic animals was analyzed by
2-test as computed on SAS software (version 8, SAS
Institute, Cary, NY).
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RESULTS |
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mRNA expression of pendrin in the kidneys of control and acidotic
rats.
In the next series of experiments, we sought to examine the effect of
metabolic acidosis on the expression of pendrin in rat kidney. Rats
were made acidotic by addition of NH4Cl to their drinking
water (see METHODS). Animals were killed, and kidney RNA
and sections were utilized for expression studies. Figure 1A is a
representative Northern blot hybridization experiment and demonstrates
that the mRNA expression of pendrin in the kidney cortex is decreased
in metabolic acidosis. The results of four samples from
separate animals, (summarized in Fig. 1B) indicate that the
expression of pendrin is decreased by 68% in acidotic rats
(n = 4, P < 0.02 vs. control rats).
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Immunofluorescent staining of pendrin in the kidneys of control and
acidotic rats.
In the next series of experiments, the effect of acidosis on pendrin
abundance was examined by indirect immunofluorescence. In kidney
sections from control rats, immunofluorescent staining with the
purified polyclonal pendrin antibody (Fig.
2A) shows apical labeling in a
subpopulation of CCD cells. Specificity of the staining is demonstrated
in Fig. 2B. As indicated, labeling was completely prevented
by preadsorption of the immune sera with the synthetic peptide. The
limited expression of pendrin in CCD is in agreement with recent
reports on the expression of pendrin in the kidney (28,
35).
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Cl/HCO
/HCO
-ICs was examined in control and acidotic
animals. Toward this end, the
-ICs and
-ICs were first identified
by their pHi response to luminal or basolateral
Cl
removal in microperfused CCDs, according to the
established criteria (see METHODS). Representative
pHi tracings in
-ICs in control and acidosis are shown
in Fig. 5, A and B,
respectively.
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DISCUSSION |
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The present experiments examine the regulation of pendrin
in metabolic acidosis in rat kidney. Functional studies in
microperfused cortical collecting tubules demonstrate that apical
Cl/HCO
-ICs
is decreased by ~60% in acid-loaded rats (Fig. 5). Northern blot hybridization experiments demonstrated that the mRNA expression of
pendrin decreased in the kidneys of acidotic animals (Fig. 1).
Similarly, immunohistochemical studies indicated decreased expression
of pendrin protein in intercalated cells of acid-loaded rats (Figs. 2
and 3). In contrast to the apical
Cl
/HCO
-ICs, the
basolateral Cl
/HCO
-ICs increased in acidosis (Fig. 6).
A Cl/HCO
-ICs and mediates the secretion of
HCO
-ICs,
-ICs express a Cl
/HCO
/HCO
-ICs is distinct from AE1 (31).
Recent findings identified pendrin as an important candidate for
an apical Cl/HCO
-ICs
(36). This conclusion was on the basis of functional and
molecular studies indicating that pendrin is an apical
Cl
/HCO
-ICs and principal cells
(28). In addition, pendrin null mice failed to secrete
HCO
/HCO
-ICs function, as concluded from changes in
H+-ATPase- and AE1-labeling patterns. The present studies
are the first to measure the apical
Cl
/HCO
-ICs
in rat kidney (Fig. 5). Furthermore, our findings demonstrating
decreased apical Cl
/HCO
-ICs (Fig. 5) are in agreement with previous
immunocytochemical data indicating adaptive regulation of
H+-ATPase in rat kidney in acidosis (5, 29,
38). The reduction in pendrin mRNA in acidosis is specific, as
judged by a lack of reduction in AQP-2 mRNA in acidosis
(3). These latter results correlate very well with
immunocytochemical labeling performed in the present studies (Fig. 4).
The reduction in apical Cl
/HCO
Rat kidney AE1 mRNA levels increased in response to both respiratory
and metabolic acidosis (11a, 18). Immunocytochemical studies indicated
adaptive upregulation of AE1 in basolateral membranes of -ICs in
acidotic rats (21, 29, 38, 43). Our results demonstrating
increased basolateral Cl
/HCO
-ICs in acidosis are in complete agreement with the
above molecular and immunocytochemical studies.
Adaptation of rabbit CCD to both in vivo and in vitro metabolic
acidosis has been studied in detail and shown to result mainly from the
decreased activity of the apical
Cl/HCO
-ICs, as well
as the increased activity of the basolateral
Cl
/HCO
-ICs and
reversal of the functional polarity of
-ICs in CCDs incubated in low
pH in vitro (26, 30, 32, 33). However, molecular identity of the Cl
/HCO
/HCO
-ICs and named it AE4. AE4 mRNA expression has also been shown in rat kidney (26), but preliminary immunocytochemical labeling from
different groups has been conflicting with respect to its subcelullar
localization in rat CCDs (12, 26). Further studies are
necessary to address this issue.
Some studies in rabbit CCDs have shown both apical and basolateral
Cl/HCO
/HCO
In conclusion, mRNA expression and protein abundance of pendrin are
downregulated in metabolic acidosis in the rat kidney, resulting in
decreased apical Cl/HCO
-ICs. Taken together, these results suggest that pendrin
plays an important role in HCO
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ACKNOWLEDGEMENTS |
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These studies were supported by a Merit Review grant from the Department of Veterans Affairs, National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-52821 and DK-54430, a Cystic Fibrosis Foundation grant, and grants from Dialysis Clinic, Inc.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Soleimani, Division of Nephrology and Hypertension, Dept. of Medicine, Univ. of Cincinnati, 231 Albert Sabin Way, MSB G259, Cincinnati, Ohio 45267-0585 (E-mail: Manoocher.Soleimani{at}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.
August 13, 2002;10.1152/ajprenal.00205.2002
Received 30 May 2002; accepted in final form 13 August 2002.
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