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Vol. 301, Issue 2, 578-585, May 2002
Department of Pharmacology and Toxicology, University Medical
Center Nijmegen, Nijmegen, The Netherlands (S.A.T., P.H.E.S., F.G.M.R.,
R.M.); Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Science, National Institutes of Health, Research
Triangle Park, North Carolina (D.S.M.); Institut für
Pharmazeutische Technologie und Biopharmazie, Heidelberg, Germany
(C.G., G.F.); Mount Desert Island Biological Laboratory, Salisbury
Cove, Maine (S.A.T., C.G., G.F., D.S.M.)
We recently demonstrated in isolated killifish renal proximal tubules
that two classes of nephrotoxicants, aminoglycoside antibiotics and
radiocontrast agents, rapidly decrease transport mediated by multidrug
resistance protein 2 (Mrp2) by causing endothelin (ET) release and
signaling through an ETB receptor and protein kinase C
(PKC) (Masereeuw et al., 2000; Terlouw et al., 2001). In the present
study, we used killifish proximal tubules, fluorescein methotrexate, a fluorescent model substrate for Mrp2, and
confocal microscopy to examine the effects of two heavy metal salts
(CdCl2 and HgCl2) on Mrp2 function. Three
patterns of effects were seen. First, exposing tubules to 10 µM
CdCl2 or 100 nM HgCl2 for 30 min reduced
Mrp2-mediated transport. This reduction was abolished by the
ETB receptor antagonist, RES-701-1, and by the
PKC-selective inhibitor, bis-indolylmaleimide I; neither of these
pharmacological tools by itself affected transport. As with
aminoglycoside antibiotics and radiocontrast agents, the acute effects
of 10 µM CdCl2 or 100 nM HgCl2 on transport
were also blocked by nifedipine, suggesting that Ca2+ also
initiated cadmium and mercury action. Second, exposure to higher
concentrations of CdCl2 and HgCl2 appeared to
be toxic. Third, exposing tubules for 6 to 24 h to lower levels of
CdCl2 increased Mrp2-mediated transport and Mrp2
immunostaining at the luminal membrane of the proximal tubule cells.
Together, these findings indicate that exposure of renal proximal
tubules to heavy metals initially leads to reduced Mrp2 function but is
followed by an induction in Mrp2-mediated transport after long-term exposure.
This article has been cited by other articles:
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