Endothelin B Receptor-Mediated Regulation of ATP-Driven Drug Secretion in Renal Proximal Tubule
- Rosalinde Masereeuw1,3,
- Sylvie A. Terlouw1,3,
- Rémon A. M. H. van Aubel1,
- Frans G. M. Russel1 and
- David S. Miller2,3
- 1Department of Pharmacology and Toxicology, University of Nijmegen, Nijmegen, The Netherlands (R.M., S.A.T., R.A.M.H. van A., F.G.M.R.);2Laboratory of Pharmacology and Chemistry, NIEHS/National Institutes of Health, Research Triangle Park, North Carolina (D.S.M.); and 3Mount Desert Island Biological Laboratory, Salisbury Cove, Maine (R.M., S.A.T., D.S.M.)
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
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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
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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
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- Received May 12, 1999.
- Accepted October 8, 1999.
- U.S. Government
