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Vol. 59, Issue 6, 1433-1440, June 2001
Department of Pharmacology and Toxicology, University Medical
Centre Nijmegen, Nijmegen, The Netherlands (S.A.T., R.M., F.G.M.R.);
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (D.S.M.); and Mount Desert Island
Biological Laboratory, Salisbury Cove, Maine (S.A.T., D.S.M.)
We previously used killifish proximal tubules, fluorescent
substrates, and confocal microscopy to demonstrate that transport mediated by the multidrug resistance protein (Mrp2) and by
P-glycoprotein was reduced by nanomolar concentrations of endothelin-1
(ET), acting through a basolateral B-type ET receptor and protein
kinase C (PKC). Here we show that representatives of two classes of
nephrotoxicants decrease transport by activating the endothelin-PKC
signaling pathway. Exposing tubules to radiocontrast agents (iohexol,
diatrizoate) or aminoglycoside antibiotics (gentamicin, amikacin)
reduced Mrp2-mediated fluorescein methotrexate (FL-MTX) transport from
cell to tubular lumen. Pretreating the tubules with an
ETB-receptor antagonist or with PKC-selective inhibitors
abolished these effects. The nephrotoxicants activated signaling by
inducing release of ET from the tubules, because adding of an antibody
against ET to the medium abolished the effects. Elevating medium
Ca2+ also reduced FL-MTX transport; this reduction was
abolished when tubules were pretreated with an ET antibody, an
ETB-receptor antagonist, PKC-selective inhibitors, or the
Ca2+ channel blocker, nifedipine. None of these drugs by
themselves affected FL-MTX transport. Importantly, nifedipine also
blocked the ETB-receptor/PKC-dependent reduction in FL-MTX
transport caused by gentamicin and diatrizoate. These results for two
classes of structurally unrelated nephrotoxicants suggest that
Ca2+-dependent ET release and subsequent action through an
autocrine mechanism may be an early response to tubular injury.
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S. A. Terlouw, C. Graeff, P. H. E. Smeets, G. Fricker, F. G. M. Russel, R. Masereeuw, and D. S. Miller Short- and Long-Term Influences of Heavy Metals on Anionic Drug Efflux from Renal Proximal Tubule J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 578 - 585. [Abstract] [Full Text] [PDF]
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 D. S. Miller, R. Masereeuw, and K. J. Karnaky Jr. Regulation of MRP2-mediated transport in shark rectal salt gland tubules Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R774 - R781. [Abstract] [Full Text] [PDF]
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S. Notenboom, D. S. Miller, P. Smits, F. G. M. Russel, and R. Masereeuw Role of NO in endothelin-regulated drug transport in the renal proximal tubule Am J Physiol Renal Physiol, March 1, 2002; 282(3): F458 - F464. [Abstract] [Full Text] [PDF]
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