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II. Department of Physiology, University of Saarland, D-66421 Homburg, Germany
1Correspondence: II. Physiologisches Institut, Universität des Saarlandes, Medizinische Fakultät, D-66421 Homburg/Saar, Germany. E-mail: frank.thevenod{at}med-rz.uni-sb.de
The mechanisms of cadmium (Cd) -dependent nephrotoxicity were studied in
a rat proximal tubule (PT) cell line. CdCl2 (5 µM)
increased the production of reactive oxygen species (ROS), as
determined by oxidation of dihydrorhodamine 123 to fluorescent
rhodamine 123. The levels of ubiquitin-conjugated cellular proteins
were increased by Cd in a time-dependent fashion (maximum at 24–48 h).
This was prevented by coincubation with the thiol antioxidant
N-acetylcysteine (NAC, 15 mM). Cd also increased apoptosis
(controls: 2.4±1.6%; Cd: 8.1±1.9%), but not necrosis
(controls: 0.5 ± 0.3%; Cd: 1.4± 2.5%). Exposure of PT cells
with Cd decreased protein levels of the catalytic subunit (
1) of
Na+/K+-ATPase, a long-lived membrane protein
(t1/2>48 h) that drives
reabsorption of ions and nutrients through Na+-dependent
transporters in PT. Incubation of PT cells for 48 h with Cd
decreased Na+/K+-ATPase 1-subunit, as
determined by immunoblotting, by 
50%, and NAC largely prevented
this effect. Inhibitors of the proteasome such as MG-132 (20 µM) or
lactacystin (10 µM), as well as lysosomotropic weak bases such as
chloroquine (0.2 mM) or NH4Cl (30 mM), significantly
reduced the decrease of Na+/K+-ATPase
1-subunit induced by Cd, and in combination abolished the effect of
Cd on Na+/K+-ATPase. Immunofluorescence
labeling of Na+/K+-ATPase showed a reduced
expression of the protein in the plasma membrane of Cd-exposed cells.
After addition of lactacystin and chloroquine to Cd-exposed PT cells,
immunoreactive material accumulated into intracellular vesicles. The
data indicate that micromolar concentrations of Cd can increase ROS
production and exert a toxic effect on PT cells. Oxidative damage
increases the degradation of Na+/K+-ATPase
through both the proteasomal and endo-/lysosomal proteolytic pathways.
Degradation of oxidatively damaged
Na+/K+-ATPase may contribute to the `Fanconi
syndrome'-like Na+-dependent transport defects associated
with Cd-nephrotoxicity.—Thévenod, F., Friedmann, J. M. Cadmium-mediated oxidative stress in kidney proximal tubule cells
induces degradation of Na+/K+-ATPase through
proteasomal and endo-/lysosomal proteolytic pathways.
Key Words: nephrotoxicity • heavy metals • oxygen radicals • Fanconi syndrome • ubiquitin
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