Published online before print August 18, 2003, doi: 10.1161/01.HYP.0000088321.67254.B7
(Hypertension. 2003;42:356.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Deoxycorticosterone Upregulates PDS (Slc26a4) in Mouse Kidney
Role of Pendrin in Mineralocorticoid-Induced Hypertension
From the Department of Medicine (J.W.V.), University of Florida College of Medicine, Gainesville; the Departments of Medicine (K.A.H., S.M.W.) and Surgery (M.-E.W.), University of Texas Medical School at Houston; the Genome Technology Branch (I.E.R., L.A.E., E.D.G.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Md; the Department of Medicine (D.M.G., S.M.W.), Emory University, Atlanta, Ga; and the Wellcome Trust Sanger Institute (L.A.E.), Hinxton, Cambridge, UK.
Correspondence to Susan M. Wall, MD, Renal Division, Emory University, WMRB Rm 338, 1639 Pierce Dr NE, Atlanta, GA 30322. E-mail smwall{at}emory.edu
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Abstract |
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Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus, Pds (Slc26a4) is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion exchange–mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether Pds mRNA and protein expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice, Pds mRNA increased 60%, whereas pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B intercalated cells and increased 6-fold in type B cells. Because pendrin transports HCO3- and Cl-, we tested whether DOCP treatment unmasks abnormalities in acid-base or NaCl balance in Pds (-/-) mice. In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in Pds (+/+) and Pds (-/-) mice. After DOCP treatment, weight gain and hypertension were observed in Pds (+/+) but not in Pds (-/-) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in Pds (-/-) than Pds (+/+) mice. We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis.
Key Words: acid-base equilibrium • hypertension, mineralocorticoid • anions • mice • ion transport
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Introduction |
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Along the renal collecting duct, secretion of acid or base occurs through intercalated cells. Whether an intercalated cell secretes or absorbs net H+ equivalents depends at least in part on whether the H+-ATPase localizes to the apical or the basolateral plasma membrane.1 Therefore, intercalated cells are also subclassified on the basis of the presence or absence of the anion exchanger, AE1, and the distribution of the H+-ATPase within the cell.2–5 Each of these intercalated cell subtypes can be identified on the basis of ultrastructural characteristics.5 Type A intercalated cells are believed to secrete H+ equivalents. However, the physiologic role of non-A, non-B intercalated cells in acid-base homeostasis is unknown.5
Rodents can ingest a substantial base load and yet develop only a mild elevation in serum HCO3-.6 The cortical collecting duct (CCD) is a critical component of the kidney’s robust ability to excrete OH- equivalents during metabolic alkalosis. In the CCD, secretion of OH- equivalents occurs in large part through the type B intercalated cell,4 wherein Cl-/HCO3- exchange across the apical plasma membrane functions in series with the H+-ATPase expressed on the basolateral plasma membrane.2,3,5 The gene product(s) responsible for this apical anion exchange–mediated HCO3- secretion has been a matter of controversy. However, recent evidence points to the Na+-independent Cl-/HCO3- exchanger Pds7,8 as a candidate gene product.
Everett and colleagues9 first reported the molecular structure of the gene disrupted in the Pendred syndrome (Pds). In the kidney, pendrin is expressed in the CCD, the connecting tubule (CNT), the initial collecting tubule (iCT), and the distal convoluted tubule (DCT).7,10,11 Within these segments, pendrin localizes to the apical plasma membrane and apical cytoplasmic vesicles of both type B and non-A, non-B intercalated cells.7,10,11 Although pendrin is highly expressed in kidney, both Pds-knockout mice (Pds -/-) and individuals with genetic disruption of the Pds gene (Pendred syndrome) have normal renal function and normal acid-base, fluid, and electrolyte balance.7 However, a renal phenotype might be unmasked in Pds (-/-) mice under conditions that upregulate Pds in normal animals.
Whether Pds expression changes in tandem with activity of the putative apical anion exchanger is now a subject of intense interest. Both apical anion-exchange activity and pendrin protein expression are upregulated after NaHCO3 ingestion.12–14 Aldosterone administration represents another model of metabolic alkalosis in which apical anion exchange is upregulated.15,16 However, the effect of aldosterone on Pds expression is unknown.
We therefore asked 3 questions: first, are Pds mRNA and protein upregulated in another model of metabolic alkalosis, ie, administration of an aldosterone analogue (deoxycorticosterone pivalate [DOCP])? Second, is the subcellular distribution of pendrin altered with DOCP administration? and finally, is a renal phenotype, such as an acid-base abnormality or dysregulation of fluid and/or electrolyte balance, unmasked with DOCP administration in Pds (-/-) mice?
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Methods |
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Animals
Series 1
Male, non-Swiss albino mice (Harlan, Ardmore, Tex) weighing 20 to 30 g were fed a balanced 0.07% Na+, 0.8% K+ diet (53881300 Zeigler Brothers) prepared as a gel. Control and treated mice, chosen at random, were given 18 g of a gelled, 0.6% agar diet for 6 days before sacrifice. Mice received 13.5 mL water and 4.5 g mouse chow supplemented with 0.7 mEq NaCl per day added to the gel. Treated mice received 1.7 mg DOCP (Ciba-Geigy Animal Health) by intramuscular injection 7 days before sacrifice.
Series 2
Pds (-/-) mice developed by Everett et al17 were bred in parallel with co-isogenic wild-type mice (129S6/SvEv Tac, Taconic Farms, Germantown, NY). For 6 days before sacrifice, age- and sex-matched Pds (+/+) and (-/-) mice were pair-fed 14 g of the gel diet supplemented with 0.8 mEq NaCl daily.
Series 3
Pds (-/-) and Pds (+/+) mice, fed as in series 2, received 1.7 mg DOCP IM 7 days before sacrifice. Mice were placed in metabolic cages, and urine was collected on ice under oil for 24 hours before sacrifice. All mice were anesthetized with 4% isoflurane in 100% O2 at 1 L/min before sacrifice. The Institutional Animal Care and Use Committee at Emory and the University of Texas Health Science Center (UTHSC) approved all animal treatment protocols.
Measurement of Blood Pressure, Serum and Urine Chemistries, and Arterial Blood Gases
Systolic blood pressure in conscious mice was measured by the tail-cuff method with use of a MOD 59 pulse amplifier (Innovators in Instrumentation) or BP-2000 (Visitech Systems). Blood was collected for serum chemistry analyses by cardiac puncture under isoflurane anesthesia. Unless noted, urine and serum chemistry values were measured with commercially available instruments (Hitachi 717 and 747 analyzers) at IDEXX Laboratories (West Sacramento, Calif). For arterial blood gases and serum K+, mice were anesthetized with isoflurane for 15 minutes before sample collection. An abdominal incision was made, and 0.15 mL blood was drawn into a heparinized syringe through the abdominal aorta. The sample was placed on ice, and arterial blood gases and K+ were measured immediately at the Hermann Hospital Clinical Laboratory on a commercially available instrument (IL 1620, Instrumentation Laboratories, or an AVL OPTI 1 Blood Gas Analyzer, AVL Medical Instruments). Urinary pH was measured immediately after collection of urine into a gas-tight syringe by bladder puncture of anesthetized mice. Urine osmolality was measured with a vapor pressure osmometer (Wescor). Urinary total ammonia concentration was measured on a continuous-flow fluorimeter18 and a kit (171-A, Sigma Chemical). Net acid excretion was taken as the sum of the 24-hour urinary excretion of total ammonia concentration plus titratable acid. Urinary HCO3- concentration was assumed to be zero. Titratable acid was calculated by using the measured urinary pH and phosphorous concentration and a pK for phosphate of 6.8.19
Preparation of Total RNA and Quantitative Real-Time RT-PCR
Total RNA was isolated from mouse kidney by using a mini-kit (Qiagen Rneasy, Qiagen).10 Quantitative real-time polymerase chain reaction (PCR) was performed in the Quantitative Genomics Core Laboratory in the Department of Integrative Biology and Pharmacology, UTHSC, with use of a sequence detector (7700 sequence detector, Applied Biosystems).10 Specific quantitative assays for mouse Pds and ß-actin were used.10 ß-Actin and Pds mRNAs were measured in the same samples and expressed per left kidney.
Antibody
The primary rabbit anti-pendrin antibody recognizes amino acids 766 to 780 of the human pendrin protein sequence. Polyclonal antibodies that target this amino acid sequence have been characterized previously in studies of mouse kidney.7
Pendrin Immunolocalization
Kidneys were preserved and processed for light and electron microscopy as described previously.10 For light microscopy, pendrin immunoreactivity was localized by routine immunoperoxidase techniques.10 For electron microscopy, pendrin immunoreactivity was localized in ultrathin sections by immunogold cytochemistry.10 The CCDs, connecting segments (CNT), and initial collecting tubules (iCT) were identified as described previously.10 Type A, type B, and non-A, non-B intercalated cell subtypes were identified by morphological characteristics established in studies of rats and mice under basal conditions.3,5,10
Morphometric Analysis
Apical plasma membrane boundary length, cytoplasmic area, and gold label along the apical plasma membrane and over the cytoplasm, including cytoplasmic vesicles, were quantified in type B intercalated cells and non-A, non-B intercalated cells10,20 in 4 to 6 individual mice from each group. A least 5 of each intercalated cell type were selected randomly in each animal and photographed at a primary magnification of 5000x and examined at a final magnification of 
18 200x. The exact magnification was calculated by using a calibration grid with 1134 lines/mm. Apical plasma membrane boundary length and cytoplasmic area were determined by using point and intersection counting, the Merz curvilinear test grid, and standard stereologic formulas.20
Statistical Analysis
For morphometric data without normal distribution or equal variance, a Mann-Whitney rank-sum test was used. In all other studies, comparisons were made between 2 groups with an unpaired Student t test. A P<0.05 indicates statistical significance. Data are displayed as mean±SEM.
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Results |
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DOCP Upregulates Pendrin mRNA in Mouse Kidney
Treatment of normal, non-Swiss albino mice with DOCP for 7 days in vivo caused systolic blood pressure to increase from 111±1 (n=7) to 132±3 mm Hg (n=10, P<0.05). Urinary pH was 6.87±0.22 (n=6) in controls versus 6.34±0.21 (n=6, P=NS) in DOCP-treated mice. Twenty-four-hour urinary ammonium excretion was 0.165±0.021 mEq (n=6) in controls versus 0.268±0.074 mEq (n=9, P=NS) in DOCP-treated mice. Whereas differences between these groups did not all reach statistical significance, the means reported are consistent with previous reports that DOCP increases blood pressure while reducing urinary pH and increasing urinary ammonium excretion.21,22
The effect of DOCP expression on Pds mRNA was examined. Pds mRNA/kidney was 4.37±0.38x109 template molecules (n=10) in controls but increased to 7.12±0.87x109 in DOCP-treated mice (n=10, P<0.05). In contrast, no difference in ß-actin mRNA/kidney was observed between controls and DOCP-treated mice (1.53±0.13x1011 template molecules in controls, n=10, versus 1.65±0.25x1011 in DOCP-treated mice, n=10). We conclude that DOCP upregulates Pds message expression in kidney.
Effect of DOCP on the Expression and Subcellular Distribution of Pendrin
We tested the effect of DOCP on pendrin protein expression and the subcellular distribution of pendrin. By immunohistochemistry and light microscopy, pendrin labeling was similar in kidneys from control and DOCP-treated mice. In kidneys from both groups, pendrin labeling was observed over the apical region of a subset of cells within the iCT and the CNT (Figures 1a and 1b), as described previously.10,11 Within the CCD, pendrin immunoreactivity was present over the apical region of a subset of cells, as described previously (Figure 2).7,10,11 However, in the apical region of cells within the CCD, pendrin labeling appeared to be more intense and more discrete in kidneys from DOCP-treated mice than in controls (Figures 2a and 2b). Thus, possible DOCP-induced changes in the subcellular distribution of pendrin were studied in more detail.
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In mouse CCDs, we had observed previously that the majority of non-A intercalated cells are type B intercalated cells.5 Thus, pendrin protein expression in the apical plasma membrane and apical cytoplasmic vesicles was quantified in type B intercalated cells from both untreated and DOCP-treated mice by immunogold cytochemistry, transmission electron microscopy, and morphometric analysis. Type B cells typically exhibit a smooth apical plasma membrane surface, numerous cytoplasmic vesicles, a subapical band free of vesicles, and abundant mitochondria (Figure 3a).10 In control animals, the ultrastructural features and distribution of pendrin immunolabel were similar to our previous observations.10 Pendrin immunoreactivity was prevalent over apical cytoplasmic vesicles, but little immunolabel was present along the apical plasma membrane (Figure 3b). However, in DOCP-treated mice, type B intercalated cells typically exhibited a marked increase in apical plasma membrane microprojections and intense pendrin immunolabel along the apical plasma membrane (Figure 4). Morphometric analysis (Table 1) demonstrated more than a 2-fold increase in apical plasma membrane boundary length in type B cells from DOCP-treated mice relative to controls, and a 2-fold increase in pendrin label density along the apical plasma membrane. Thus, a 6-fold increase in pendrin immunolabel along the apical plasma membrane of the type B cell was measured. Moreover, the ratio of immunolabel in the apical plasma membrane to label in the cytoplasm and cytoplasmic vesicles increased 8-fold. However, no significant change in total pendrin labeling in type B intercalated cells was noted in mice treated with DOCP. We conclude that DOCP treatment induces a marked shift in the subcellular distribution of pendrin in the type B intercalated cell of the CCD, resulting in increased expression of pendrin in the apical plasma membrane with little change in total pendrin protein expression per cell.
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The effect of DOCP on the distribution of pendrin in non-A, non-B intercalated cells differed from its effect in type B intercalated cells (Table 1). In non-A, non-B intercalated cells from mice treated with DOCP, boundary length did not change; however, pendrin label in the apical plasma membrane increased 2-fold owing to increased density of pendrin labeling. Moreover, total pendrin label per cell was increased 2-fold in this cell type.
We conclude that pendrin apical plasma membrane label density is increased by DOCP treatment to a similar extent in type B intercalated cells and in non-A, non-B intercalated cells. However, pendrin expression in the apical plasma membrane is increased to a greater extent in type B intercalated cells than in non-A, non-B cells because of the marked increase in apical plasma membrane boundary length that occurs in the type B cell after administration of this aldosterone analogue.
Effect of DOCP on Pds (+/+) and Pds (-/-) Mice
Because pendrin is upregulated with DOCP, further studies investigated whether a renal phenotype is unmasked in Pds (-/-) mice treated with aldosterone analogues (Figures 5 and 6
and Table 2). In the absence of DOCP, after 7 days of paired intake of the gelled diet, systolic blood pressure was similar in Pds (-/-) and Pds (+/+) mice. Moreover, weight was unchanged in both groups over the treatment period (Figure 5). When mice were treated with DOCP and then ate the gelled diet for 6 days, wild-type mice gained weight and became hypertensive, whereas Pds (-/-) mice treated with DOCP had no change in blood pressure and did not gain weight, despite an identical intake of the diet during this period (79.2±2.9 g, Pds (+/+); 78.8±2.3 g, Pds (-/-); P=NS, Figure 5). Table 2 shows that serum electrolytes and 24-hour urinary NaCl excretion were the same in wild-type and Pds (-/-) mice 7 days after administration of DOCP. Thus, pendrin is critical in the process of DOCP-induced hypertension and weight gain.
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Because pendrin transports HCO3-,8 arterial blood gases were measured in Pds (-/-) and (+/+) mice. In the absence of DOCP, arterial pH and calculated HCO3- were similar in both groups. After DOCP treatment, both Pds (+/+) and Pds (-/-) mice developed metabolic alkalosis. However, the metabolic alkalosis was more severe in DOCP-treated Pds (-/-) mice. Seven days after DOCP treatment, Pds (-/-) mice had a lower urinary pH than did wild-type mice, although net acid excreted over 24 hours was similar. We conclude that pendrin attenuates DOCP-induced metabolic alkalosis.
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Discussion |
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Aldosterone is critical to the regulation of both net acid secretion and absorption of NaCl along the collecting duct. In the CCD, aldosterone administration in vivo leads to increased secretion of HCO3- and K+. Aldosterone administration in vivo also increases absorption of NaCl through upregulation of the Na+ channel ENaC,23 the thiazide-sensitive NaCl cotransporter,24 and the Na,K-ATPase,25 which causes Na+ retention and increased blood pressure. Which renal Cl- transporters are regulated by aldosterone is poorly understood. Moreover, the extent to which aldosterone-induced hypertension occurs through changes in Cl- transporter expression in the kidney is unknown.26 To our knowledge, this study is the first to show a role for a Cl- transporter in aldosterone-induced hypertension.
Administration of aldosterone in vivo induces a dramatic increase in both Cl- absorption and HCO3- secretion in the CCD. After DOC administration in vivo, the Cl- concentration in the collected luminal fluid of rabbit CCD drops to 89 mEq/L from perfusate values of 112 mEq/L,27 whereas collected HCO3- concentration increases from 25 to >40 mmol/L.15 Most transepithelial Cl- transport in this segment occurs either through paracellular transport or through transepithelial transport across intercalated cells, rather than across principal cells.28 Across intercalated cells, aldosterone-stimulated, active Cl- absorption occurs through apical Cl-/HCO3- exchange in series with a basolateral Cl- conductance.4
There is growing evidence that pendrin contributes to the apical anion exchange process of the type B intercalated cell. Both pendrin and the putative apical anion exchanger of the type B intercalated cell transport Cl- and HCO3-.8,29 Both apical anion-exchange activity and pendrin protein expression are downregulated in models of metabolic acidosis, eg, with NH4Cl ingestion,12–14,30,31 and are upregulated in models of metabolic alkalosis, eg, with NaHCO3 ingestion.12–14 Apical anion exchange in the CCD is also upregulated by DOCP.15,16,32,33 This study is the first to demonstrate regulation of pendrin by an aldosterone analogue. After DOCP treatment, we observed a 6-fold increase in pendrin immunoreactivity in the apical plasma membrane of the type B intercalated cell and a 2-fold increase in the apical plasma membrane of the non-A, non-B intercalated cell. This observation is consistent with previous reports that demonstrated greater change in pendrin expression in the type B intercalated cell than in the non-A, non-B cell with changes in acid-base balance.14
Aldosterone administered in vivo is a well-established model of hypokalemic metabolic alkalosis. Thus, DOCP might upregulate pendrin indirectly through hypokalemia and/or metabolic alkalosis. However, in another model of hypokalemic metabolic alkalosis (dietary K+ restriction), pendrin expression is reduced in the apical plasma membrane.13 Thus, pendrin is not upregulated in all models of hypokalemic metabolic alkalosis. However, whether the effect of DOCP pendrin expression is a direct effect of the hormone or an indirect effect, such as through changes in vascular volume, will require examination of other treatment models.
Apical Na+-independent Cl-/HCO3- exchange of the type B cell and pendrin participate in secretion of OH- equivalents during metabolic alkalosis.7,33 In mice treated with DOCP and ingesting NaHCO3, secretion of HCO3- in the CCD is Pds dependent.7 During metabolic alkalosis, CCD from wild-type, Pds (+/+) mice secrete HCO3-.7 However, CCDs from Pds (-/-) mice absorbed HCO3- when studied under the same treatment conditions.7 In the present study, we observed that after DOCP treatment, Pds (-/-) mice had a more severe metabolic alkalosis than did wild-type mice, consistent with the defect in secretion of OH- equivalents demonstrated previously in the CCD of Pds (-/-) mice.7
We observed that Pds (+/+) mice treated with DOCP gained weight and developed hypertension. However, pair-fed, DOCP-treated Pds (-/-) mice did not become hypertensive and did not gain weight. This DOCP resistance likely occurred because of the inability of the DCT, CNT, and CCD of Pds (-/-) mice to absorb Cl- fully. However, this hypothesis requires further study. Abnormalities in fluid absorption and secretion have been observed in other organ systems with disruption of the Pds gene. Patients with the Pendred syndrome and Pds-knockout mice have deafness and structural abnormalities of the inner ear, including endolymphatic hydrops.17 In both the inner ear and kidney, pendrin might participate in the absorption of Cl-. The functional absence of pendrin might lead to loss of Cl- in the urine and retention of Cl- in the endolymphatic fluid of the ear. The endolymphatic sac of the ear contains mitochondria-rich, type A–like cells that express the H-ATPase on the apical plasma membrane and type B–like cells that express pendrin on the apical plasma membrane.34 Thus, cells of the endolymphatic sac resemble renal intercalated cells both ultrastructurally and functionally.34
It is likely that with 7 days of DOCP treatment, the cumulative excretion of NaCl and net acid differ in Pds (+/+) and (-/-) mice. However, because 24-hour urinary NaCl and net acid excretion did not differ between the 2 groups of mice after 7 days of DOCP treatment, differences in excretion most likely occurred within the first 6 days of DOCP administration.
In conclusion, Pds protein and mRNA expression are upregulated in parallel in mouse kidney after DOCP administration. Moreover, DOCP treatment increases expression of pendrin in the apical plasma membrane in non-A, non-B and type B intercalated cells. Pendrin attenuates aldosterone-induced metabolic alkalosis by augmenting secretion of OH- equivalents. Pendrin-dependent Cl- uptake likely contributes to aldosterone-induced fluid retention and hypertension.
Perspectives
The present study is the first to demonstrate a role for pendrin in mineralocorticoid-induced hypertension. Moreover, this study raises the possibility that pendrin could be the target of future antihypertensive and/or diuretic drugs.
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Acknowledgments |
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This work was supported by the National Institute of Digestive, Diabetes and Kidney Diseases grant DK 52935 (to S.M. Wall). We thank Mae De La Calzada, Department of Medicine, University of Texas Medical School, Houston, and Melissa A. Lewis, Sharon W. Matthews, and John C. Bitter, University of Florida College of Medicine Electron Microscopy Core Facility, Gainesville, Fla, for their technical assistance. We thank Dr Greg Shipley, Department of Integrative Biology, UTHMC, for his suggestions, and Dr. Robert Beach, Department of Medicine, University of Texas Medical Branch, Galveston, Texas, for his assistance.
Received May 9, 2003; first decision June 3, 2003; accepted July 16, 2003.
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References |
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1. Brown D, Hirsch S, Gluck S. Localization of a proton-pumping ATPase in rat kidney. J Clin Invest. 1988; 82: 2114–2126.[Medline] [Order article via Infotrieve]
2. Alper SL, Natale J, Gluck S, Lodish HF, Brown D. Subtypes of intercalated cells in rat kidney collecting duct defined by antibodies against erythroid band 3 and renal vacuolar H+-ATPase. Proc Natl Acad Sci U S A. 1989; 86: 5429–5433.
3. Kim J, Kim Y-H, Cha J-H, Tisher CC, Madsen KM. Intercalated cell subtypes in connecting tubule and cortical collecting duct of rat and mouse. J Am Soc Nephrol. 1999; 10: 1–12.
4. Schuster VL. Function and regulation of collecting duct intercalated cells. Annu Rev Physiol. 1993; 55: 267–288.[CrossRef][Medline] [Order article via Infotrieve]
5. Teng-ummnuay P, Verlander JW, Yuan W, Tisher CC, Madsen KM. Identification of distinct subpopulations of intercalated cells in the mouse collecting duct. J Am Soc Nephrol. 1996; 7: 260–274.[Abstract]
6. Good DW. Adaptation of HCO3- and NH4+ transport in rat MTAL: effects of chronic metabolic acidosis and Na+ intake. Am J Physiol. 1990; 258: F1345–F1353.
7. Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED. Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. Proc Natl Acad Sci U S A. 2001; 98: 4221–4226.
8. Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE. Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex. Am J Physiol. 2001; 280: F356–F364.
9. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997; 17: 411–422.[CrossRef][Medline] [Order article via Infotrieve]
10. Wall SM, Hassell KA, Royaux IE, Green ED, Chang JY, Shipley GL, Verlander JW. Localization of pendrin in mouse kidney. Am J Physiol. 2003; 284: F229–F241.
11. Kim Y-H, Kwon T-HFS, Kim J, Tisher CC, Madsen KM, Nielsen S. Immunocytochemical localization of pendrin in intercalated cell subtypes in rat and mouse kidney. Am J Physiol. 2002; F744–F754.
12. McKinney TD, Burg MB. Bicarbonate transport by rabbit cortical collecting tubules. J Clin Invest. 1977; 60: 766–768.[Medline] [Order article via Infotrieve]
13. Wagner CA, Finberg KE, Stehberger PA, Lifton RP, Giebisch GH, Aronson PS, Geibel JP. Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney by acid-base status. Kidney Int. 2002; 62: 2109–2117.[CrossRef][Medline] [Order article via Infotrieve]
14. Frische S, Kwon T-H, Frokiaer J, Madsen KM, Nielsen S. Regulated expression of the collecting duct anion exchanger pendrin in response to chronic NH4Cl or NaHCO3 loading in rats. Am J Physiol. 2003; 284: F584–F593.
15. Knepper MA, Good DW, Burg MB. Mechanism of ammonia secretion by cortical collecting ducts of rabbits. Am J Physiol. 1984; 247: F729–F738.
16. Garcia-Austt J, Good DW, Burg MB, Knepper MA. Deoxycorticosterone-stimulated bicarbonate secretion in rabbit cortical collecting duct: effects of luminal chloride removal and in vivo acid loading. Am J Physiol. 1985; 249: F205–F212.
17. Everett LA, Belyantseva IA, Noben-Trauth K, Cantos R, Chen A, Thakkar SI, Hoogstraten-Miller SL, Kachar B, Wu DK, Green ED. Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet. 2001; 10: 153–161.
18. Wall SM. NH4+ augments net acid secretion by a ouabain-sensitive mechanism in isolated perfused inner medullary collecting ducts. Am J Physiol. 1996; 270: F432–F439.[Medline] [Order article via Infotrieve]
19. Lemann J Jr, Lennon EJ. A potential error in the measurement of urinary titratable acid. J Lab Clin Med. 1966; 67: 906–913.[Medline] [Order article via Infotrieve]
20. Weibel ER, Bolender RP. Stereological techniques for electron microscopic morphometry. In: Hayat MA, ed. Principles and Techniques of Electron Microscopy. New York, NY: Van Nostrand Reinhold Co Ltd; 1973: 237–296.
21. Wall SM, Sands JM, Flessner MF, Nonoguchi H, Spring KR, Knepper MA. Net acid transport by isolated perfused inner medullary collecting ducts. Am J Physiol. 1990; 258: F75–F84.[Medline] [Order article via Infotrieve]
22. Welbourne TC, Francoeur D. Influence of aldosterone on renal ammonia production. Am J Physiol. 1977; 233: E56–E60.[Medline] [Order article via Infotrieve]
23. Eaton DC, Malik B, Saxena NC, Al-Khalili OK, Yue G. Mechanisms of aldosterone’s action on epithelial Na+ transport. J Membrane Biol. 2001; 184: 313–319.[CrossRef][Medline] [Order article via Infotrieve]
24. Kim G-H, Masilamani S, Turner R, Mitchell C, Wade JB, Knepper MA. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci U S A. 1998; 95: 14552–14557.
25. Ewart HS, Klip A. Hormonal regulation of the Na+-K+-ATPase: mechanisms underlying rapid and sustained changes in pump activity. Am J Physiol. 1995; 269: C295–C311.
26. Ornellas DS, Nascimento DS, Christoph DH, Guggino WM, Morales MM. Aldosterone and high-NaCl diet modulate ClC-2 chloride channel gene expression in rat kidney. Pflugers Arch. 2002; 444: 193–201.[CrossRef][Medline] [Order article via Infotrieve]
27. Hanley MJ, Kokko JP. Study of chloride transport across the rabbit cortical collecting tubule. J Clin Invest. 1978; 62: 39–44.[Medline] [Order article via Infotrieve]
28. Schlatter E, Greger R, Schafer JA. Principal cells of cortical collecting ducts of the rat are not a route of transepithelial Cl- transport. Pflugers Arch. 1990; 417: 317–323.[CrossRef][Medline] [Order article via Infotrieve]
29. Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet. 1999; 21: 440–443.[CrossRef][Medline] [Order article via Infotrieve]
30. Petrovic S, Wang Z, Ma L, Soleimani M. Regulation of the apical Cl-/HCO3- exchanger pendrin in rat cortical collecting duct in metabolic acidosis. Am J Physiol. 2003; 284: F103–F112.
31. Schwartz GJ, Tsuruoka S, Vijayakumar S, Petrovic S, Mian A, Al-Awqati Q. Acid incubation reverses the polarity of intercalated cell transporters, an effect mediated by hensin. J Clin Invest. 2002; 109: 89–99.[CrossRef][Medline] [Order article via Infotrieve]
32. Knepper MA, Good DW, Burg MB. Ammonia and bicarbonate transport by rat cortical collecting ducts perfused in vitro. Am J Physiol. 1985; 249: F870–F877.
33. Star RA, Burg MB, Knepper MA. Bicarbonate secretion and chloride absorption by rabbit cortical collecting ducts: role of chloride/bicarbonate exchange. J Clin Invest. 1985; 76: 1123–1130.[Medline] [Order article via Infotrieve]
34. Peters TA, Tonnaer ELGM, Kuijpers W, Cremers CWRJ, Curfs JHJ. Differences in endolymphatic sac mitochondria-rich cells indicate specific functions. Laryngoscope. 2002; 112: 534–541.[CrossRef][Medline] [Order article via Infotrieve]
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  Y. H. Kim, T. D. Pham, W. Zheng, S. Hong, C. Baylis, V. Pech, W. H. Beierwaltes, D. B. Farley, L. E. Braverman, J. W. Verlander, et al. Role of pendrin in iodide balance: going with the flow Am J Physiol Renal Physiol, October 1, 2009; 297(4): F1069 - F1079. [Abstract] [Full Text] [PDF]
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 P. Hafner, R. Grimaldi, P. Capuano, G. Capasso, and C. A. Wagner Pendrin in the mouse kidney is primarily regulated by Cl- excretion but also by systemic metabolic acidosis Am J Physiol Cell Physiol, December 1, 2008; 295(6): C1658 - C1667. [Abstract] [Full Text] [PDF]
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 Y. Nakagami, S. Favoreto Jr, G. Zhen, S.-W. Park, L. T. Nguyenvu, D. A. Kuperman, G. M. Dolganov, X. Huang, H. A. Boushey, P. C. Avila, et al. The Epithelial Anion Transporter Pendrin Is Induced by Allergy and Rhinovirus Infection, Regulates Airway Surface Liquid, and Increases Airway Reactivity and Inflammation in an Asthma Model J. Immunol., August 1, 2008; 181(3): 2203 - 2210. [Abstract] [Full Text] [PDF]
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L. Adler, E. Efrati, and I. Zelikovic Molecular mechanisms of epithelial cell-specific expression and regulation of the human anion exchanger (pendrin) gene Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1261 - C1276. [Abstract] [Full Text] [PDF]
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 V. Pech, W. Zheng, T. D. Pham, J. W. Verlander, and S. M. Wall Angiotensin II Activates H+-ATPase in Type A Intercalated Cells J. Am. Soc. Nephrol., January 1, 2008; 19(1): 84 - 91. [Abstract] [Full Text] [PDF]
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F. Lang, V. Vallon, M. Knipper, and P. Wangemann Functional significance of channels and transporters expressed in the inner ear and kidney Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1187 - C1208. [Abstract] [Full Text] [PDF]
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Y. H. Kim, V. Pech, K. B. Spencer, W. H. Beierwaltes, L. A. Everett, E. D. Green, W. Shin, J. W. Verlander, R. L. Sutliff, and S. M. Wall Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1314 - F1324. [Abstract] [Full Text] [PDF]
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J. W. Verlander The thiazide-sensitive NaCl cotransporter: a new target for acute regulation of salt and water transport by angiotensin II Am J Physiol Renal Physiol, September 1, 2007; 293(3): F660 - F661. [Full Text] [PDF]
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K. Y. Na, G.-H. Kim, K. W. Joo, J. W. Lee, H. R. Jang, Y. K. Oh, U. S. Jeon, S.-W. Chae, M. A. Knepper, and J. S. Han Chronic furosemide or hydrochlorothiazide administration increases H+-ATPase B1 subunit abundance in rat kidney Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1701 - F1709. [Abstract] [Full Text] [PDF]
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S. de Seigneux, H. Malte, H. Dimke, J. Frokiaer, S. Nielsen, and S. Frische Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1256 - F1266. [Abstract] [Full Text] [PDF]
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V. Pech, Y. H. Kim, A. M. Weinstein, L. A. Everett, T. D. Pham, and S. M. Wall Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism Am J Physiol Renal Physiol, March 1, 2007; 292(3): F914 - F920. [Abstract] [Full Text] [PDF]
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W. Zheng, J. W. Verlander, I. J. Lynch, M. Cash, J. Shao, L. R. Stow, B. D. Cain, I. D. Weiner, S. M. Wall, and C. S. Wingo Cellular distribution of the potassium channel KCNQ1 in normal mouse kidney Am J Physiol Renal Physiol, January 1, 2007; 292(1): F456 - F466. [Abstract] [Full Text] [PDF]
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J. W. Verlander, Y. H. Kim, W. Shin, T. D. Pham, K. A. Hassell, W. H. Beierwaltes, E. D. Green, L. Everett, S. W. Matthews, and S. M. Wall Dietary Cl- restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells Am J Physiol Renal Physiol, October 1, 2006; 291(4): F833 - F839. [Abstract] [Full Text] [PDF]
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M. Vallet, N. Picard, D. Loffing-Cueni, M. Fysekidis, M. Bloch-Faure, G. Deschenes, S. Breton, P. Meneton, J. Loffing, P. S. Aronson, et al. Pendrin Regulation in Mouse Kidney Primarily Is Chloride-Dependent J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2153 - 2163. [Abstract] [Full Text] [PDF]
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D. Loffing-Cueni, S. Y. Flores, D. Sauter, D. Daidie, N. Siegrist, P. Meneton, O. Staub, and J. Loffing Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1264 - 1274. [Abstract] [Full Text] [PDF]
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 N. Shcheynikov, Y. Wang, M. Park, S. B.H. Ko, M. Dorwart, S. Naruse, P. J. Thomas, and S. Muallem Coupling Modes and Stoichiometry of Cl-/HCO3- Exchange by slc26a3 and slc26a6 J. Gen. Physiol., April 24, 2006; 127(5): 511 - 524. [Abstract] [Full Text] [PDF]
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S. M. Wall, M. A. Knepper, K. A. Hassell, M. P. Fischer, A. Shodeinde, W. Shin, T. D. Pham, J. W. Meyer, J. N. Lorenz, W. H. Beierwaltes, et al. Hypotension in NKCC1 null mice: role of the kidneys Am J Physiol Renal Physiol, February 1, 2006; 290(2): F409 - F416. [Abstract] [Full Text] [PDF]
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Y.-H. Kim, J. W. Verlander, S. W. Matthews, I. Kurtz, W. Shin, I. D. Weiner, L. A. Everett, E. D. Green, S. Nielsen, and S. M. Wall Intercalated cell H+/OH- transporter expression is reduced in Slc26a4 null mice Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1262 - F1272. [Abstract] [Full Text] [PDF]
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 M. N. Chernova, L. Jiang, D. J. Friedman, R. B. Darman, H. Lohi, J. Kere, D. H. Vandorpe, and S. L. Alper Functional Comparison of Mouse slc26a6 Anion Exchanger with Human SLC26A6 Polypeptide Variants: DIFFERENCES IN ANION SELECTIVITY, REGULATION, AND ELECTROGENICITY J. Biol. Chem., March 4, 2005; 280(9): 8564 - 8580. [Abstract] [Full Text] [PDF]
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S. Watanabe, S. Tsuruoka, S. Vijayakumar, G. Fischer, Y. Zhang, A. Fujimura, Q. Al-Awqati, and G. J. Schwartz Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin Am J Physiol Renal Physiol, January 1, 2005; 288(1): F40 - F47. [Abstract] [Full Text] [PDF]
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F. Quentin, R. Chambrey, M. M. Trinh-Trang-Tan, M. Fysekidis, M. Cambillau, M. Paillard, P. S. Aronson, and D. Eladari The Cl-/HCO3- exchanger pendrin in the rat kidney is regulated in response to chronic alterations in chloride balance Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1179 - F1188. [Abstract] [Full Text] [PDF]
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 S. M. Wall, Y. H. Kim, L. Stanley, D. M. Glapion, L. A. Everett, E. D. Green, and J. W. Verlander NaCl Restriction Upregulates Renal Slc26a4 Through Subcellular Redistribution: Role in Cl- Conservation Hypertension, December 1, 2004; 44(6): 982 - 987. [Abstract] [Full Text] [PDF]
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