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Dietary Cl^– restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells

¹Department of Medicine, University of Florida College of Medicine, Gainesville, Florida; ²Department of Medicine, Emory University, Atlanta, Georgia; ³Department of Medicine, University of Texas, Health Science Center at Houston, Houston, Texas; ⁴Hypertension and Vascular Research Division, Henry Ford Hospital and Wayne State School of Medicine, Detroit, Michigan; ⁵Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; and ⁶The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom

Submitted 29 November 2005 ; accepted in final form 3 April 2006

	ABSTRACT

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Pendrin, encoded by Slc26a4, is a Cl^–/HCO₃^– exchanger expressed in the apical region of type B and non-A, non-B intercalated cells, which regulates renal NaCl excretion. Dietary Cl^– restriction upregulates total pendrin protein expression. Whether the subcellular expression of pendrin and whether the apparent vascular volume contraction observed in Slc26a4 null mice are Cl^– dependent, but Na⁺ independent, is unknown. Thus the subcellular distribution of pendrin and its role in acid-base and fluid balance were explored using immunogold cytochemistry and balance studies of mice ingesting a NaCl-replete or a Na⁺-replete, Cl^–-restricted diet, achieved through substitution of NaCl with NaHCO₃. Boundary length and apical plasma membrane pendrin label density each increased by 60–70% in type B intercalated cells, but not in non-A, non-B cells, whereas cytoplasmic pendrin immunolabel increased 60% in non-A, non-B intercalated cells, but not in type B cells. Following either NaCl restriction or Cl^– restriction alone, Slc26a4 null mice excreted more Cl^– and had a higher arterial pH than pair-fed wild-type mice. In conclusion, 1) following dietary Cl^– restriction, apical plasma membrane pendrin immunolabel increases in type B intercalated cells, but not in non-A, non-B intercalated cells; and 2) pendrin participates in the regulation of renal Cl^– excretion and arterial pH during dietary Cl^– restriction.

acid-base and fluid balance; mammalian collecting duct

Total pendrin protein expression in kidney is thought to depend on intake of Cl^– rather than intake of cations (15). Quentin et al. (15) measured total pendrin protein expression in rats following a high-NaCl diet and following substitution of dietary Na⁺ with K⁺ or NH₄⁺ and with substitution of Cl^– with HCO₃^–. Pendrin protein expression, they observed, is inversely correlated with Cl^– balance, such that pendrin expression increases as Cl^– balance becomes more negative. These investigators concluded that the critical regulator of pendrin total protein expression is Cl^– balance.

During dietary NaCl restriction, apical plasma membrane pendrin immunolabel increases. This increase in apical plasma membrane pendrin expression occurs entirely through subcellular redistribution of the protein rather than through increased total protein expression (23). However, Frische et al. (4) observed that following selective dietary Cl^– restriction, total pendrin protein expression increases without changes in the subcellular distribution of pendrin. Thus we were prompted to study the subcellular distribution of pendrin following selective dietary Cl^– restriction in greater detail. We also asked whether Cl^– restriction alone generates apparent vascular volume contraction and metabolic alkalosis in Slc26a4 null mice, similar to observations following restriction of both Na⁺ and Cl^– (23). Thus the purpose of the present study was to determine whether substitution of dietary NaCl with NaHCO₃ upregulates pendrin through subcellular redistribution. A second objective was to determine whether Slc26a4 null mice have a compromised ability to conserve Cl^– after ingesting a NaCl-restricted or a Na⁺-replete, Cl^–-restricted diet, which results in signs of vascular volume contraction.

	METHODS

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Animals. In series 1, male, non-Swiss albino mice (Harlan, Ardmore, TX) weighing 20–30 g were divided into two groups at random. One group received a balanced, NaCl-restricted diet (0.13 meq/day Cl^–, no. 53881300, Zeigler Brothers, Gardners, PA) for 7 days prepared as a gel (0.6% agar, 74.6% water, and 24.8% mouse chow), supplemented with NaHCO₃ (1 meq/day Na⁺, 0.13 meq/day Cl^–). The other group was pair fed the same gel diet but supplemented with NaCl instead of NaHCO₃ (NaCl-replete diet, 1 meq/day NaCl). In immunohistochemistry studies, mice were given 1.5 meq/day NaCl or 1.5 meq/day Na⁺, 0.13 meq/day Cl^– for 7 days given as a gel. In series 2, Slc26a4 (–/–) mice developed by Everett et al. (3) were bred in parallel with coisogenic wild-type mice (129S6/SvEv Tac, Taconic Farms, Germantown, NY). Age- and sex-matched Slc26a4 (+/+) and (–/–) mice were pair fed the gel diet supplemented with NaHCO₃ (0.13 meq/day Cl^–, 1 meq/day Na⁺) or NaCl (1 meq NaCl/day) for 7 days before death. In series 1 and 2, mice were placed in metabolic cages and urine was collected under mineral oil at 4°C on day 7 of the treatment period (i.e., for 24 h just before death). Mice were killed under anesthesia with 1–2% isofluorane in 100% O₂ at 1 liter/min. The Institutional Animal Care and Use Committee at Emory and the University of Texas Health Science Center (UTHSC), Houston, TX, approved all animal treatment protocols.

Measurement of blood pressure, serum and urine chemistries, aldosterone and arterial blood gases. Blood was collected for serum chemistries through the abdominal aorta under isofluorane anesthesia. Urine Cl^– concentration was determined by coulombometric titration with a CMT 10 Chloride Titrator (Radiometer, Westlake, OH) or a Chloride Analyzer 926S (Nelson Jameson, Marshfield, WI). Otherwise, serum and urine chemistries and urinary pH were measured as reported previously (21). Arterial blood gases were measured as described previously (21), using an AVL, OPTI 1 Blood Gas Analyzer (AVL Medical Instruments, Saint-Ouen L'Aumone, France) or an ABL5 (Radiometer). Plasma renin concentration was measured using methods described previously (12). Serum aldosterone was measured at the Cardiovascular Pharmacology Research Laboratory, University of Iowa College of Pharmacy, using a Coat-A-Count aldosterone radioimmunoassay (RIA) kit (Diagnostic Products, Los Angeles, CA).

Preparation of total RNA and quantitative real-time RT-PCR. Total RNA was isolated from mouse kidney as reported previously (22). Quantitative real-time PCR was performed in the Quantitative Genomics Core Laboratory in the Department of Integrative Biology and Pharmacology, UTHSC, using specific quantitative assays for mouse Slc26a4and -actin mRNA, as reported previously (22).

Antibody. The primary rabbit anti-Slc26a4 antibody recognizes amino acids 766–780 of the human Slc26a4 protein sequence. Polyclonal antibodies that target this amino acid sequence have been characterized previously in studies of mouse kidney (16).

Immunohistochemistry. Kidneys were preserved by in vivo perfusion fixation and embedded in polyester wax as described previously (21). Pendrin immunoreactivity was detected using immunoperoxidase procedures. Blocking was done with 3% H₂O₂ in water for 30 min, followed by protein blocking using 10% normal goat serum for 30 min, followed by blocking with Mouse Detective (Biocare Medical, Concord, CA) for 45 min. The anti-pendrin antibody was diluted 1:1,000 in PBS with 5% normal goat serum. The secondary antibody was a polymer-linked peroxidase-conjugated goat anti-rabbit IgG (MACH2, Biocare Medical, Walnut Creek, CA).

Immunogold cytochemistry. Kidneys were prepared for electron microscopy as described previously (22). For electron microscopy, Slc26a4 immunoreactivity was localized in ultrathin sections using immunogold cytochemistry (22). The cortical collecting duct (CCD), connecting segments (CNT), and initial collecting tubules were identified as described previously (22). Type A, type B, and non-A, non-B intercalated cell subtypes were identified using morphological characteristics established in studies of rat and mouse under basal conditions (22). Type B cells are typically rounded with an eccentric nucleus, clustered mitochondria, a smooth apical plasma membrane, and numerous cytoplasmic vesicles distributed throughout the cell, including the basal region of the cell. Type B cells often have a vesicle-free band of cytoplasm along the apical plasma membrane. Non-A, non-B cells have a very high mitochondrial density and prominent apical plasma membrane microprojections. Cytoplasmic vesicles are relatively few, are distributed almost exclusively in the apical cytoplasm, and have more electron-dense limiting membranes compared with type B intercalated cell vesicles.

Samples were imaged using a Zeiss EM10 transmission electron microscope fitted with a Peltier-cooled CCD camera (SIA-7C) controlled by Maxim DL software (Scientific Instruments and Applications, Atlanta, GA).

Morphometric analysis. Apical plasma membrane boundary length and cytoplasmic area were determined for entire cell profiles in type B and non-A, non-B intercalated cells from each treatment group using similar methods to those described previously (22). In each animal, at least five cells of each intercalated cell subtype were selected at random and photographed at a primary magnification of x5,000 and examined at a final magnification of x20,200. The exact magnification was determined and standardized using a calibration grid with 2,160 lines/mm. For calculation of label densities, gold label along a test area of the apical plasma membrane and over the apical cytoplasm, including cytoplasmic vesicles, were quantified using digital images of the apical regions of the cells photographed at a primary magnification of 12,500 and framed to include a maximal sample of luminal surface and cytoplasm. For counting, these images were enlarged to 68,000, with the precise magnification determined by a calibration grid. About 25–28% of total cell cytoplasm was imaged, whereas 53–59% of the apical plasma membrane per cell profile was imaged. As for the entire cell profiles, apical plasma membrane boundary length and cytoplasmic area were determined by point and intersection counting using the Merz curvilinear test grid. Gold particles associated with the respective compartments were counted and correlated with the membrane boundary length and cytoplasmic area of the sample images. Raw data from individual images were pooled to produce a single value for each parameter in each mouse. For each parameter, the mean value for each mouse studied was used in the statistical analysis. The n represents the number of mice studied.

Statistical analysis. For morphometric data without normal distribution or equal variance, a Mann-Whitney rank sum U-test was used. In all other studies, comparisons were made between two groups using an unpaired Student's t-test. A P < 0.05 indicates statistical significance. Data are displayed ± SE.

	RESULTS

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Effect of Cl^– restriction on arterial pH, plasma renin activity, and serum aldosterone. Dietary supplementation with NaHCO₃ generates high dietary Na⁺ intake with low intake of Cl^–. Because dietary ingestion of NaHCO₃ has been used as a model of metabolic alkalosis, the effect of dietary substitution of Cl^– with HCO₃^– on arterial pH was explored (Table 1). As shown, arterial pH and circulating aldosterone concentrationwere unchanged with dietary substitution of Cl^– with HCO₃^–. However, plasma renin concentration increased threefold following dietary Cl^– restriction, consistent with previous reports in rat (8). Therefore, in wild-type mice, supplementing the diet with NaHCO₃ provides a model of high dietary Na⁺ intake with low-Cl^– intake, which increases circulating renin concentration without generating alkalemia or changing circulating aldosterone.

We explored whether this treatment model increases pendrin immunolabel (Fig. 1). Within the CNT, the predominant pendrin-positive cell is the non-A, non-B cell (20). Figure 1 shows that pendrin immunoreactivity within the CNT covers a broader apical region of labeled cells in mice ingesting the Na⁺-replete, Cl^–-restricted diet compared with cells from mice ingesting the NaCl-replete mice (Fig. 1, a and b). No consistent differences in pendrin immunoreactivity were observed between the experimental groups at the light microscopic level within the CCD, where the type B intercalated cell is the predominant pendrin-positive cell type (Fig. 1, c and d) (20).

View larger version (128K): [in this window] [in a new window]   Fig. 1. Light microscopy of cortex from wild-type mice ingesting a NaCl-replete or a Na+-replete, Cl–-restricted diet. Mice were given 1.5 meq NaCl/day or 1.5 meq Na+, 0.13 meq/day Cl– for 7 days given as a gelled diet. Sections of cortex labeled for pendrin from mice on the NaCl-replete (a and c) and from mice on the Na+-replete, Cl–-restricted diets (b and d) are shown. Pendrin immunoreactivity within the connecting segments (CNT; arrows) covers a broader apical region of labeled cells in mice ingesting the Na+-replete, Cl–-restricted diet compared with cells from mice ingesting the NaCl-replete mice (aand b). No consistent difference in pendrin immunoreactivity (arrows) was observed between the experimental groups at the light microscopic level within the cortical collecting duct (CCD; c and d).

View larger version (60K): [in this window] [in a new window]   Fig. 2. Transmission electron micrograph of type B intercalated cells labeled for pendrin from mice on a NaCl-replete (1 meq NaCl/day) or a Na+-replete, Cl–-restricted diet (1 meq/day Na+, 0.13 meq/day Cl–). A: cell from a mouse on a NaCl-replete diet. Pendrin immunogold label was mainly located over apical cytoplasmic vesicles (arrows). B: cell from a mouse on a Na+-replete, Cl–-restricted diet. This type B intercalated cell shows increased pendrin immunolabel in the apical plasma membrane (arrows).

View larger version (64K): [in this window] [in a new window]   Fig. 3. Transmission electron micrograph of non-A, non-B intercalated cells labeled for pendrin from mice on a NaCl-replete or a Na+-replete, Cl–-restricted diet. A: cell from a mouse on a NaCl-replete diet (1 meq/day NaCl). Pendrin immunogold label was located over apical cytoplasmic vesicles (arrows) and the apical plasma membrane. B: cell from a mouse on a Na+-replete, Cl–-restricted diet (1 meq/day Na+, 0.13 meq/day Cl–). This non-A, non-B intercalated cell shows increased pendrin immunolabel over cytoplasmic vesicles (arrows).

View larger version (132K): [in this window] [in a new window]   Fig. 4. Transmission electron micrograph of a principal cell labeled for pendrin. Only rare gold particles were observed over principal cells. Fewer than 2 gold particles per test area were observed in this cell type.

View larger version (13K): [in this window] [in a new window]   Fig. 5. Cumulative urinary Cl– excretion after introducing a NaCl-restricted or a Na+-replete, Cl–-restricted diet. Slc26a4 (+/+) and Slc26a4 (–/–) mice were pair fed a NaCl-replete diet for 3 days (0.78 meq/day NaCl, days –2 to 0). On days 1-7, mice were given either a Na+-replete, Cl–-restricted diet (1 meq/day Na+, 0.13 meq/day Cl–; A) or a NaCl-restricted diet (0.13 meq/day NaCl; B). On days 0-7, 24-h urinary Cl– excretion was measured.

Despite the higher plasma renin concentration and the greater Cl^– excretion observed in Slc26a4 null relative to wild-type mice, serum aldosterone was not higher in these mutant mice. Why serum aldosterone does not increase in tandem with increased renin concentration is not clear and will require further studies.

Slc26a4 (–/–), but not Slc26a4 (+/+), mice develop metabolic alkalosis following NaHCO₃ ingestion. Because wild-type mice do not develop metabolic alkalosis upon dietary substitution of NaCl with NaHCO₃, we asked whether this treatment protocol generates metabolic alkalosis in Slc26a4 null mice. Table 3 shows that after 7 days of dietary NaHCO₃ supplementation, arterial pH and calculated HCO₃^– are slightly higher in Slc26a4 null than wild-type mice. Thus Slc26a4 null mice develop a mild metabolic alkalosis with restriction of either NaCl or Cl^– alone (23) (Table 3).

	DISCUSSION

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Numerous studies demonstrated the importance of renal Na⁺ transporters such as the Na⁺ channel, ENaC (2), and the thiazide-sensitive NaCl cotransporter (TSC/NCC) (5) in the renal regulation of fluid balance. Intake of Na⁺, rather than Cl^–, is thought to be the ion responsible for the increase in vascular volume which follows ingestion of salt. However, in humans and rodent models of salt-sensitive hypertension, such as with administration of aldosterone analogs [deoxycorticosterone (DOCP)] and a high-salt diet, vascular volume and blood pressure vary more with intake of Cl^– than with intake of Na⁺ (9, 10). These observations raise the possibility that renal Cl^– transporters are critical to NaCl balance and hence the regulation of vascular volume. Our laboratory showed that apparent vascular volume and blood pressure are critically dependent on the expression of the Cl^–/HCO₃^– exchanger, pendrin (21, 23).

During dietary restriction of both Na⁺ and Cl^–, pendrin expression in the apical plasma membrane increases in type B, but not in non-A, non-B, intercalated cells. In this treatment model, apical plasma membrane pendrin label density in type B cells increases entirely through subcellular protein redistribution and is not accompanied by changes in boundary length (23). However, during selective dietary Cl^– restriction, apical plasma membrane pendrin label increases in type B intercalated cells, through both increased pendrin label density and increased boundary length.

The present study shows that the increased pendrin total protein expression observed previously during dietary Cl^– restriction (23) originates, at least in part, from non-A, non-B intercalated cells. Following selective dietary Cl^– restriction, we observed increased total cytoplasmic pendrin immunolabel per cell in non-A, non-B intercalated cells, without a change in cell size. However, the increased cytoplasmic pendrin label density observed in non-A, non-B cells was not accompanied by increased apical plasma membrane pendrin immunolabel. Why pendrin immunolabel increased in cytoplasmic vesicles, but not in the apical plasma membrane, is curious. Following Cl^– restriction, non-A, non-B intercalated cells may provide a reservoir of pendrin protein available on demand for insertion into the apical plasma membrane, such as following increased circulating aldosterone. However, the function of this increased cytoplasmic pendrin expression, remains to be determined.

The present and previous studies demonstrated that Slc26a4 mRNA and total protein increase with a Na⁺-replete, Cl^–-restricted diet, but not with a NaCl-restricted diet (23). Quentin et al. (15) concluded that during NaCl restriction, the rats studied did not develop a sufficiently net negative Cl^– balance to upregulate total pendrin protein expression. However, following moderate dietary restriction of both Na⁺ and Cl^– or restriction of Cl^– alone, we observed an increase in apical plasma membrane pendrin immunolabel in type B cells (23). Because the abundance of type B and non-A, non-B intercalated cells differs in rat and mouse kidney, we cannot exclude the possibility, however, that species-specific differences exist (6, 20).

Because the expression and subcellular distribution of pendrin were not identical following restriction of NaCl and restriction of Cl^– alone, the subcellular distribution of pendrin responds to stimuli other than changes in Cl^– balance. Dietary intake of HCO₃^– has a variety of effects on renal function such as a transient increase in glomerular filtration rate and increased Na⁺ excretion (11). Thus pendrin protein expression may be regulated directly or indirectly through changes in intake of HCO₃^–. NaHCO₃ administration increases urinary and sometimes arterial PCO₂ (1). In CCDs perfused in vitro, increased PCO₂ stimulates apical Cl^–/HCO₃^– exchange of the type B intercalated cell (13). Chronic increases in urinary and/or renal interstitial PCO₂ may augment pendrin protein synthesis, particularly in non-A, non-B intercalated cells. However, other explanations are also possible and will require further studies.

Nevertheless, a Na⁺-replete, Cl^–-restricted diet and a Na⁺- and Cl^–-restricted diet produce a similar renal phenotype in Slc26a4 null mice. Following either diet, Slc26a4 null mice are in greater net negative Cl^– balance. Moreover, Slc26a4 null mice have a slightly higher arterial pH than wild-type mice during dietary Cl^– restriction. While the goiter and hearing loss typical of persons with Pendred syndrome have been well characterized over the past century, the metabolic alkalosis and the apparent vascular volume contraction observed in mice with genetic disruption of Slc26a4have not been observed in persons with disease-producing mutations. Further studies are needed to characterize the acid-base and fluid and electrolyte balance of these persons under conditions which stimulate pendrin expression and unmask differences between wild-type and Slc26a4 null mice, such as following NaCl restriction or following restriction of Cl^– alone.

In conclusion, during either dietary NaCl restriction or restriction of Cl^– alone, apical plasma membrane pendrin immunolabel is increased in type B, but not in non-A, non-B intercalated cells. Following dietary Cl^– restriction, Slc26a4 null mice excrete more Cl^– and develop a more pronounced metabolic alkalosis than wild-type mice, most likely due to the reduced ability of the former to absorb Cl^– and secrete HCO₃^–.

	GRANTS

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This project was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-52935 (to S. M. Wall).

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. M. Wall, Renal Division, Emory Univ. School of Medicine, WMB Rm. 338, 1639 Pierce Dr. NE, Atlanta, GA 30322 (e-mail: smwall{at}emory.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.

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