Abstract
This article is a review on recent studies in intact renal proximal tubules that link tubular nephrotoxicants with endothelin (ET) regulation of xenobiotic export pump function. The data show that transport on p-glycoprotein and Mrp2 decreases rapidly when ET signals through an ET(B) receptor, NO synthase (NOS), and protein kinase C (PKC). Surprisingly, nephrotoxicants, such as radiocontrast agents, aminoglycoside antibiotics, and heavy metal salts, "hijack" this signaling pathway, causing ET release from the tubules, hormone binding to its receptor, activation of NOS and PKC, and reduced xenobiotic transport. These findings suggest a new common mechanism by which nephrotoxicants may act to disrupt renal tubular function.
Copyright 2002 Wiley Periodicals, Inc.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Biological Transport / drug effects*
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Biological Transport / physiology
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Calcium / metabolism
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Endothelins / metabolism*
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Fluoresceins / toxicity*
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Kidney Tubules, Proximal / drug effects*
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Kidney Tubules, Proximal / metabolism*
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Killifishes
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Membrane Transport Proteins*
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Methotrexate / analogs & derivatives
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Methotrexate / toxicity*
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / drug effects
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Nitric Oxide / metabolism
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Protein Kinase C / metabolism
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Receptor, Endothelin B
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Receptors, Endothelin / drug effects*
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Signal Transduction / drug effects
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Xenobiotics / pharmacokinetics*
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Endothelins
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Fluoresceins
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Membrane Transport Proteins
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Receptor, Endothelin B
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Receptors, Endothelin
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Xenobiotics
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Nitric Oxide
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Protein Kinase C
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Calcium
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multidrug resistance-associated protein 1
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Methotrexate