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The Thiazide-Sensitive Na–Cl Cotransporter Is an Aldosterone-Induced Protein (Fludrocortisone͞sodium Chloride Transport͞distal Convoluted Tubule͞collecting Duct)

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The Thiazide-Sensitive Na–Cl Cotransporter Is an Aldosterone-Induced Protein (Fludrocortisone͞sodium Chloride Transport͞distal Convoluted Tubule͞collecting Duct) Proc. Natl. Acad. Sci. USA Vol. 95, pp. 14552–14557, November 1998 Physiology The thiazide-sensitive Na–Cl cotransporter is an aldosterone-induced protein (fludrocortisoneysodium chloride transportydistal convoluted tubuleycollecting duct) GHEUN-HO KIM*, SHYAMA MASILAMANI*, RACHEL TURNER*, CARTER MITCHELL*, JAMES B. WADE*†, AND MARK A. KNEPPER*‡ *Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and †Department of Physiology, University of Maryland College of Medicine, Baltimore, MD 21201 Edited by Robert W. Berliner, Yale University School of Medicine, New Haven, CT, and approved September 14, 1998 (received for review August 5, 1998) ABSTRACT Although the collecting duct is regarded as situ hybridization (9) and reverse transcription–PCR (10), it the primary site at which mineralocorticoids regulate renal was concluded that TSC mRNA is found virtually exclusively sodium transport in the kidney, recent evidence points to the in the distal convoluted tubule in the rat kidney. Immunohis- distal convoluted tubule as a possible site of mineralocorticoid tochemical studies using fusion protein-derived antibodies to action. To investigate whether mineralocorticoids regulate the TSC also have demonstrated that expression of the TSC expression of the thiazide-sensitive Na–Cl cotransporter protein in the rat kidney is limited to the distal convoluted (TSC), the chief apical sodium entry pathway of distal con- tubule cells (11). voluted tubule cells, we prepared an affinity-purified, peptide- We hypothesize here that aldosterone may act on the distal directed antibody to TSC. On immunoblots, the antibody convoluted tubule to increase the expression of the TSC of the recognized a prominent 165-kDa band in membrane fractions distal convoluted tubule. To address this hypothesis, we have from the renal cortex but not from the renal medulla. Immu- developed a peptide-derived polyclonal antibody to TSC. nofluorescence immunocytochemistry showed TSC labeling Using this antibody, we have carried out immunoblotting and only in distal convoluted tubule cells. Semiquantitative im- immunofluorescence experiments demonstrating that in- munoblotting studies demonstrated a large increase in TSC creases in circulating levels of mineralocorticoids, whether expression in the renal cortex of rats on a low-NaCl diet (207 6 achieved by dietary NaCl restriction or mineralocorticoid 21% of control diet). Immunofluorescence localization in administration, result in a marked increase in TSC protein tissue sections confirmed the strong increase in TSC expres- expression in the distal convoluted tubule. Thus, the TSC of sion. Treatment of rats for 10 days with a continuous subcu- the renal distal convoluted tubule appears to be an important taneous infusion of aldosterone also increased TSC expression target for aldosterone-mediated regulation of renal sodium (380 6 58% of controls). Furthermore, 7-day treatment of rats chloride excretion. with an orally administered mineralocorticoid, fludrocorti- 6 sone, increased TSC expression (656 114% of controls). We METHODS conclude that the distal convoluted tubule is an important site of action of the mineralocorticoid aldosterone, which strongly Polyclonal Antibodies. A 24-aa synthetic peptide corre- up-regulates the expression of TSC. sponding to amino acids 104–126 of the amino-terminal tail of the rat TSC (with an added amino-terminal cysteine) was The mineralocorticoid hormone aldosterone regulates urinary produced by standard solid-phase peptide synthesis techniques sodium excretion by increasing the rate of renal epithelial (sequence: NH2-DGRPGHELTDGLVEDETGANSEKC- sodium absorption (1). It is widely held that the major site of COOH). Analysis using the BLAST computer program showed aldosterone action in the mammalian kidney is the cortical no significant overlap of the immunizing peptide with any collecting duct, where aldosterone regulates apical sodium known eukaryotic protein, including related cotransporters entry via the amiloride-sensitive epithelial sodium channel expressed in kidney and other epithelial tissues. The peptide (1–3). However, the results of recent renal micropuncture was purified by HPLC and was conjugated to maleimide- studies (4) and studies of [3H]metolazone binding in renal activated keyhole limpet hemocyanin via covalent linkage to cortical membranes (4, 5) suggest that the distal convoluted the amino-terminal cysteine. Two rabbits were immunized tubule is an additional renal tubule site of mineralocorticoid with this conjugate by using a combination of Freund’s com- plete and incomplete adjuvants. The rabbits developed ELISA action. Apical sodium entry into the distal convoluted tubule . is mediated by a thiazide-sensitive Na–Cl cotransporter (TSC) titers 1:32,000 prior to exsanguination. One of these antisera (6). Thus, it is likely that putative actions of aldosterone to (L573) was used for the present studies after affinity purifi- regulate sodium transport in the distal convoluted tubule cation on a column made with the same synthetic peptide used would result from regulation of the thiazide-sensitive Na–Cl for immunizations (SulfoLink Antibody Immobilization kit, entry pathway. Pierce). Initial characterization of the antibody was achieved Investigation of the function and regulation of the TSC has by using membrane fractions obtained by differential centrif- been facilitated by the recent cloning of cDNAs for the ugation carried out as described (12). A previously character- cotransporter from flounder bladder (7) and rat kidney (8), ized rabbit polyclonal antibody to the Na–K–2Cl cotransporter which has led to the development of molecular tools for of the thick ascending limb (13) was used for control immu- localization of TSC expression. Based on experiments using in noblots. In addition, a rabbit polyclonal anti-TSC antibody (14) The publication costs of this article were defrayed in part by page charge This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: TSC, thiazide-sensitive Na–Cl cotransporter; BW, payment. This article must therefore be hereby marked ‘‘advertisement’’ in body weight. accordance with 18 U.S.C. §1734 solely to indicate this fact. ‡To whom reprint requests should be addressed at: National Institutes 0027-8424y98y9514552-6$0.00y0 of Health, Building 10, Room 6N260, 10 Center Drive MSC 1603, PNAS is available online at www.pnas.org. Bethesda, MD 20892-1603. e-mail: [email protected]. 14552 Downloaded by guest on September 27, 2021 Physiology: Kim et al. Proc. Natl. Acad. Sci. USA 95 (1998) 14553 raised to a bacterial fusion protein corresponding to a portion mgy200 g BW), the base rat chow (15 gy200 g BW), and 0.5% of the amino-terminal tail of rat TSC (kindly provided by D. H. agar. For the treated rats, fludrocortisone (Sigma) was dis- Ellison, University of Colorado) was used to confirm the key solved in water at a concentration of 50 mgyliter, and was used findings made with our anti-TSC antibody. in making the gelled diet. The dose of fludrocortisone corre- For immunocytochemistry, the present studies also utilized sponded to 1.2 mgy200 g BW per day. After 7 days of monospecific affinity-purified antibodies to the bumetantide- treatment, the rats were killed for semiquantitative immuno- sensitive Na1–K1–2Cl2 cotransporter of the thick ascending blotting as described below. limb and to the Na1–Ca21 exchanger, a connecting-tubule Immunoblotting. Semiquantitative immunoblotting was car- marker. The Na1–K1–2Cl2 cotransporter antibody is a ried out as described (17) to assess relative expression levels of chicken polyclonal antibody (LC20) raised to a synthetic TSC using whole homogenates from whole kidneys of the rats peptide corresponding to amino acids 33–55 of the rat co- prepared as described above under Animals and Experimental transporter, based on the sequence published by Gamba et al. Protocols. In brief, whole kidneys were homogenized by using (7). This antibody gave complete overlap of labeling with our a tissue homogenizer (Omni 1000 fitted with a micro-sawtooth previously characterized rabbit polyclonal antibody to the generator) in ice-cold isolation solution (pH 7.6) containing Na1–K1–2Cl2 cotransporter (13) in double-labeling experi- 250 mM sucrose, 10 mM triethanolamine (Calbiochem), 1 ments in rat (data not shown). The antibody to the Na1–Ca21 mgyml leupeptin (Bachem), and 0.1 mgyml phenylmethylsul- exchanger is mouse mAb (Affinity BioReagents, Golden, CO). fonyl fluoride (United States Biochemical), and total protein Animals and Experimental Protocols. Pathogen-free male concentration (bicinchoninic acid (BCA) kit; Pierce) was Sprague–Dawley rats (Taconic Farms) weighing 180–220 g adjusted to 1.2 mgyml with isolation solution. The samples were were used in this study. solubilized in 53 Laemmli sample buffer (1 vol per 4 vol of Dietary NaCl restriction study. Dietary sodium restriction for sample) followed by heating to 60°C for 15 minutes. Initial 10 days was used to produce a physiological increase in Coomassie blue-stained SDSypolyacrylamide gels confirmed circulating aldosterone level. All rats were maintained on a that samples were matched with regard to protein content. gelled diet, based on an approach originally described by For immunoblotting, SDSyPAGE was carried out using Bouby et al. (15). The gelled diet contained all nutrients and minigels of 7.5% polyacrylamide, and proteins were trans- all
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