Localization of NBC1 Variants in Rat Kidney

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Abstract

Na+-HCO3– cotransporter (NBC1) plays a major role in bicarbonate reabsorption from proximal tubules. In a previous immunohistochemical study on human kidney, we showed that the kidney-type transporter (kNBC1) was abundantly expressed in the basolateral membranes of proximal tubules while the expression of pancreatic-type transporter (pNBC1) was undetectable. In the present study we tried to determine the localization of NBC1 variants in rat kidney using the antibodies against the unique N-terminal regions of kNBC1 and pNBC1. In Western blot analysis on the membrane-enriched fraction from rat kidney both anti-kNBC1 and anti-pNBC1 antibodies yielded a ∼130 kDa band. In immunohistochemical analysis with confocal microscopy the anti-kNBC1 antibody produced a strong and exclusively basolateral labeling in proximal tubules. On the other hand, the occasional pNBC1 labeling was detected in the apical membranes of proximal tubules. The electron microscopic observation further supported the basolateral localization of kNBC1 as well as the localization of pNBC1 on the basis of the brush border. Acute metabolic acidosis did not change the protein expression levels as well as the intracellular distribution of both NBC1 variants in rat kidney. These results are consistent with a view that kNBC1 is the dominant variant that mediates bicarbonate reabsorption from rat renal proximal tubules. They also indicate that species difference may exist regarding the distribution of NBC1 variants in kidney.

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Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger.

Patrick Schultheis, Lane L Clarke, Pierre Meneton … (1998)

NHE3 is one of five plasma membrane Na+/H+ exchangers and is encoded by the mouse gene Slc9a3. It is expressed on apical membranes of renal proximal tubule and intestinal epithelial cells and is thought to play a major role in NaCl and HCO3- absorption. As the distribution of NHE3 overlaps with that of the NHE2 isoform in kidney and intestine, the function and relative importance of NHE3 in vivo is unclear. To analyse its physiological functions, we generated mice lacking NHE3 function. Homozygous mutant (Slc9a3-/-) mice survive, but they have slight diarrhoea and blood analysis revealed that they are mildly acidotic. HCO3- and fluid absorption are sharply reduced in proximal convoluted tubules, blood pressure is reduced and there is a severe absorptive defect in the intestine. Thus, compensatory mechanisms must limit gross perturbations of electrolyte and acid-base balance. Plasma aldosterone is increased in NHE3-deficient mice, and expression of both renin and the AE1 (Slc4a1) Cl-/HCO3- exchanger mRNAs are induced in kidney. In the colon, epithelial Na+ channel activity is increased and colonic H+,K+-ATPase mRNA is massively induced. These data show that NHE3 is the major absorptive Na+/H+ exchanger in kidney and intestine, and that lack of the exchanger impairs acid-base balance and Na+-fluid volume homeostasis.

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Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter.

Emile L. Boulpaep, M Hediger, Walter Boron … (1997)

Bicarbonate transporters are the principal regulators of pH in animal cells, and play a vital role in acid-base movement in the stomach, pancreas, intestine, kidney, reproductive system and central nervous system. The functional family of HCO3- transporters includes Cl- -HCO3- exchangers, three Na+/HCO3- cotransporters, a K+/HCO3- cotransporter, and a Na+-driven Cl- -HCO3- exchanger. Molecular information is sparse on HCO3- transporters, apart from Cl- -HCO3- exchangers ('anion exchangers'), whose complementary DNAs were cloned several years ago. Attempts to clone other HCO3- transporters, based on binding of inhibitors, protein purification or homology with anion exchangers, have so far been unsuccessful. Here we monitor the intracellular pH and membrane voltage in Xenopus oocytes to follow the expression of the most electrogenic transporter known: the renal 1:3 electrogenic Na+/HCO3- cotransporter from the salamander Ambystoma tigrinum. We now report the successful cloning and characterization of a cDNA encoding a cation-coupled HCO3- transporter. The encoded protein is 1,035 amino acids long with several potential membrane-spanning domains. We show that when it is expressed in Xenopus oocytes, this protein is electrogenic, Na+ and HCO3- dependent, and blocked by the anion-transport inhibitor DIDS, and conclude that it is the renal electrogenic sodium bicarbonate cotransporter (NBC).

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A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.

Dganit Dinour, Min-Hwang Chang, Jun-ichi Satoh … (2004)

In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na+/HCO3- cotransporter (NBCe1/SLC4A4). Recently, human genetics revealed that NBCe1 is the major renal contributor to this process. Homozygous point mutations in NBCe1 cause proximal renal tubular acidosis (pRTA), glaucoma, and cataracts (Igarashi, T., Inatomi, J., Sekine, T., Cha, S. H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G., and Endou, H. (1999) Nat. Genet. 23, 264-266). We have identified and functionally characterized a novel, homozygous, missense mutation (S427L) in NBCe1, also resulting in pRTA and similar eye defects without mental retardation. To understand the pathophysiology of the syndrome, we expressed wild-type (WT) NBCe1 and S427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO3- transport) and membrane currents using microelectrodes. HCO3- -elicited currents for S427L were approximately 10% of WT NBCe1, and CO2-induced acidification was approximately 4-fold faster. Na+ -dependent HCO3- transport (currents and acidification) was also approximately 10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO3-, indicating that under physiological ion gradient conditions, NaHCO3 could not move out of cells as is needed for renal HCO3- absorption and ocular pressure homeostasis. I-V analysis without Na+ further shows that the S427L-mediated NaHCO3 efflux mode is depressed or absent. These experiments reveal that voltage- and Na+ -dependent transport by S427L-hkNBCe1 is unfavorably altered, thereby causing both insufficient HCO3- absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).

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Author and article information

Journal

Journal ID (publisher-id): NEP

Journal ID (nlm-ta): Nephron Physiol

Journal ID (doi): 10.1159/issn.1660-2137

Title: Nephron Physiology

Publisher: S. Karger AG

ISSN (Electronic): 1660-2137

Publication date Subscription-year: 2006

Publication date (Print): September 2006

Publication date (Electronic): 28 September 2006

Volume: 104

Issue: 2

Pages: p87-p94

Affiliations

^aDepartment of Internal Medicine, Faculty of Medicine, Tokyo University; ^bDepartment of Urology, Omori Red Cross Hospital, Tokyo; ^cDepartment of Experimental Nursing, Faculty of Nursing, Fukuoka Prefectural University, Fukuoka; ^dDepartment of Anatomy, Kyorin University School of Medicine, and ^eDepartment of Urology, Musashino Red Cross Hospital, Tokyo, Japan

Article

Publisher ID: 94003 Other ID: Nephron Physiol 2006;104:p87–p94

DOI: 10.1159/000094003

PubMed ID: 16785749

SO-VID: 6dc32780-6d6a-4ded-9e9d-92bf27985403

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 05 August 2005

Date accepted : 04 February 2006

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Figures: 7, References: 38, Pages: 1

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Localization of NBC1 Variants in Rat Kidney

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Abstract

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Karger: Nephrology

Most cited references 15

Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger.

Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter.

A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.

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