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Research ArticleArticle

Endothelin B Receptor-Mediated Regulation of ATP-Driven Drug Secretion in Renal Proximal Tubule

Rosalinde Masereeuw, Sylvie A. Terlouw, Rémon A. M. H. van Aubel, Frans G. M. Russel and David S. Miller
Molecular Pharmacology January 2000, 57 (1) 59-67;
Rosalinde Masereeuw
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Sylvie A. Terlouw
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Rémon A. M. H. van Aubel
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Frans G. M. Russel
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David S. Miller
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Abstract

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ETB receptor antagonist but not by an ETA receptor antagonist. Immunostaining with an antibody to mammalian ETB receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ETB receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.

Footnotes

  • Send reprint requests to: Rosalinde Masereeuw, Ph.D., Dept. of Pharmacology and Toxicology 233, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail:R.Masereeuw{at}farm.kun.nl

  • This work was supported by a travel grant from the Netherlands Organization for Scientific Research (NWO) to R.M. Part of this work was presented at Experimental Biology '99 and published as preliminary abstracts in Bull Mt Desert Island Biol Lab [Masereeuw et al. (1998) 37:93–94, and Masereeuw et al. (1999)38:51–52].

  • Abbreviations:
    ET
    endothelin
    ABC
    ATP-binding cassette
    BIM
    bisindolylmaleimide
    ECE
    endothelin-converting enzyme
    FL
    fluorescein
    FL-MTX
    fluorescein-methotrexate
    LTC4
    leukotriene C4
    Mrp2
    multidrug resistance-associated protein 2
    NBD-CSA
    [N-ε(4-nitrobenzofurazan-7-yl)-d-Lys8]cyclosporin A
    Oat-k1/-k2
    kidney-specific organic anion transporters
    Oatp1
    organic anion transport protein
    4α-PDD
    4α-phorbol-12,13-didecanoate
    PKC
    protein kinase C
    PKA
    protein kinase A
    PMA
    phorbol-12-myristate-13-acetate
    Sf6c
    sarafotoxin 6c
    • Received May 12, 1999.
    • Accepted October 8, 1999.
  • U.S. Government
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Molecular Pharmacology: 57 (1)
Molecular Pharmacology
Vol. 57, Issue 1
1 Jan 2000
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Research ArticleArticle

Endothelin B Receptor-Mediated Regulation of ATP-Driven Drug Secretion in Renal Proximal Tubule

Rosalinde Masereeuw, Sylvie A. Terlouw, Rémon A. M. H. van Aubel, Frans G. M. Russel and David S. Miller
Molecular Pharmacology January 1, 2000, 57 (1) 59-67;

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Research ArticleArticle

Endothelin B Receptor-Mediated Regulation of ATP-Driven Drug Secretion in Renal Proximal Tubule

Rosalinde Masereeuw, Sylvie A. Terlouw, Rémon A. M. H. van Aubel, Frans G. M. Russel and David S. Miller
Molecular Pharmacology January 1, 2000, 57 (1) 59-67;
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