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J Biol Chem, Vol. 275, Issue 3, 1887-1896, January 21, 2000
From the Departments of Cadmium-mediated toxicity of cultured proximal
tubule (PT) cells is associated with increased production of reactive
oxygen species (ROS) and apoptosis. We found that
cadmium-dependent apoptosis (Hoechst 33342 and annexin V
assays) decreased with prolonged CdCl2 (10 µM) application (controls: 2.4 ± 1.6%; 5 h:
+5.1 ± 2.3%, 20 h: +5.7 ± 2.5%, 48 h: +3.3 ± 1.0% and 72 h: +2.1 ± 0.4% above controls), while cell
proliferation was not affected. Reduction of apoptosis correlated with
a time-dependent up-regulation of the drug efflux pump
multidrug resistance P-glycoprotein (mdr1) in cadmium-treated cells
(
Up-regulation of Multidrug Resistance P-glycoprotein via Nuclear
Factor-
B Activation Protects Kidney Proximal Tubule Cells from
Cadmium- and Reactive Oxygen Species-induced Apoptosis*
§,,
Physiology II and
¶ Experimental Surgery, University of Saarland, 66421 Homburg and
the Department of Nephrology, J. W. Goethe University,
Zentrum Innere Medizin, 60590 Frankfurt/Main, Germany
4-fold after 72 h), as determined by immunoblotting with the
monoclonal antibody C219 and measurement of intracellular accumulation
of the fluorescent probe calcein ± the mdr1 inhibitor PSC833 (0.5 µM). When mdr1 inhibitors (PSC833, cyclosporine A,
verapamil) were transiently added to cells with mdr1 up-regulation by
pretreatment for 72 h with cadmium, cadmium-induced apoptosis
increased significantly and to a percentage similar to that obtained in
cells with no mdr1 up-regulation (72-h cadmium: 5.2 ± 0.9%
versus 72-h cadmium + 1-h PSC833: 7.2 ± 1.4%;
p 
0.001). Cadmium-induced apoptosis and mdr1
up-regulation depended on ROS, since co-incubation with the ROS
scavengers N-acetylcysteine (15 mM) or
pyrrolidine dithiocarbamate (0.1 mM) abolished both
responses. Moreover, cadmium- and ROS-associated mdr1 up-regulation was
linked to activation of the transcription factor NF-
B;
N-acetylcysteine, pyrrolidine dithiocarbamate, and the
IB-
kinase inhibitor Bay 11-7082 (20 µM) prevented
both, mdr1 overexpression and degradation of the inhibitory NF-B
subunit, IB-, induced by cadmium. The data show that 1)
cadmium-mediated apoptosis in PT cells is associated with ROS
production, 2) ROS increase mdr1 expression by a process involving
NF-B activation, and 3) mdr1 overexpression protects PT cells
against cadmium-mediated apoptosis. These data suggest that mdr1
up-regulation, at least in part, provides anti-apoptotic protection for
PT cells against cadmium-mediated stress.
*
This work was supported by Deutsche Forschungsgemeinschaft
Grants Th 345/6-1 and Ha 1719/2-2 (to F. T. and I. A. H.) and a grant-in-aid from Fujisawa GmbH Germany.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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