Regulation of Tubular Cell MCP-1 Production by Intracellular Ions: A Role for Sodium and Calcium

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Abstract

Proximal tubule cells (PTC) in chronic renal disease produce chemokines which cause renal interstitial inflammation, and also transport more Na+ than normal. To investigate whether these two events might be related, monocyte chemoattractant protein-1 (MCP-1) production was examined in rat PTC in primary culture. Amiloride reduced, while ouabain increased levels of MCP-1 mRNA and protein. Amiloride reduced MCP-1 in cells stimulated with ouabain, lipopolysaccharide (LPS) or albumin. Intracellular Na+ rose with ouabain, but not LPS or albumin. Effects of amiloride, ouabain, LPS and albumin were abrogated by sodium-free but not chloride-free culture medium, and were not explained by changes in intracellular pH. Intracellular Ca2+ rose with ouabain, LPS or albumin and sodium-free medium. BAPTA-AM reduced intracellular Ca2+ and MCP-1 mRNA levels in unstimulated cells, and cells stimulated with ouabain, LPS or albumin. Thus, amiloride and ouabain may alter tubular cell MCP-1 by changing intracellular Na+, with secondary changes in intracellular Ca2+, whereas stimulation by LPS and albumin may involve Ca2+ directly.

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Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation.

C. Zoja, R Donadelli, G. Remuzzi … (1998)

Abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity possibly linked to the subsequent process of proximal tubular reabsorption. Here we investigated in vitro the effect of protein overload on proximal tubular cell production of RANTES, a nuclear factor-kappa B (NF-kappa B)-dependent chemokine with potent chemotactic activity for monocytes/macrophages and T lymphocytes. Confluent pig LLC-PK1 cells were incubated for 24 and 48 hours with Eagle's MEM plus 0.5% FCS containing bovine serum albumin (BSA, 1 to 30 mg/ml). Tumor necrosis factor-alpha (TNF-alpha; 100 U/ml) was used as a positive control. RANTES was measured in cell supernatants by ELISA. Bovine serum albumin (BSA) induced a time- and dose-dependent increase in proximal tubular cell RANTES production. Selected experiments using transwells showed that the RANTES release was predominantly basolateral. The stimulatory effect on tubular RANTES was not specific to albumin but was shared by immunoglobulin (Ig) G. We then explored the role of NF-kappa B on BSA-induced RANTES. The NF-kappa B inhibitors pyrrolidine dithiocarbamate (PDTC; 25 microM) and sodium salicylate (10 mM) significantly reduced BSA-induced RANTES production. Electrophoretic mobility shift assay of nuclear extracts of LLC-PK1 exposed to BSA revealed an intense NF-kappa B activation as early as 30 minutes in a dose-dependent fashion, which was inhibited by PDTC. Supershift analysis revealed that the protein subunits of activated NF-kappa B were p65/p65 homodimer, p65/cRel, p50/p65 heterodimers. Given its chemotactic activity, RANTES released into the interstitium might promote inflammatory cell recruitment and contribute to interstitial inflammation and renal disease progression.

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Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2001

Publication date (Print): June 2001

Publication date (Electronic): 23 April 2001

Volume: 9

Issue: 3

Pages: 205-213

Affiliations

Department of Renal Medicine, The University of Sydney at Westmead Hospital, Westmead, N.S.W., Australia

Article

Publisher ID: 52613 Other ID: Exp Nephrol 2001;9:205–213

DOI: 10.1159/000052613

PubMed ID: 11340305

SO-VID: ce5b9c35-e449-42a5-869b-c6b670c81618

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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.

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Regulation of Tubular Cell MCP-1 Production by Intracellular Ions: A Role for Sodium and Calcium

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Karger: Nephrology

Most cited references 1

Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation.

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