RT Journal Article
SR Electronic
T1 Nephrotoxicants Induce Endothelin Release and Signaling in Renal Proximal Tubules: Effect on Drug Efflux
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1433
OP 1440
DO 10.1124/mol.59.6.1433
VO 59
IS 6
A1 Sylvie A. Terlouw
A1 Rosalinde Masereeuw
A1 Frans G. M. Russel
A1 David S. Miller
YR 2001
UL http://molpharm.aspetjournals.org/content/59/6/1433.abstract
AB 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.