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© 1998 Oxford University Press
research-article |
Susceptibility of MT-Null Mice to Chronic CdCl2-Induced Nephrotoxicity Indicates That Renal Injury Is Not Mediated by the CdMT Complex1
Center for Environmental and Occupational Health, Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center Kansas City, Kansas 66160-7417
Received April 13, 1998; accepted July 8, 1998
Chronic human exposure to Cd results in kidney injury. It has been proposed that nephrotoxicity produced by chronic Cd exposure is via the Cd-metallothionein complex (CdMT) and not by inorganic forms of Cd. If this hypothesis is correct, then MT-null mice, which cannot form CdMT, should not develop nephrotoxicity. Control and MT-null mice were injected sc with a wide range of CdCl2 doses, six times/week for up to 10 weeks, and their renal Cd burden, renal MT concentration, and nephrotoxicity were quantified. In control mice, renal Cd burden increased in a dose-and time-dependent manner, reaching as high as 140 µg Cd/g kidney, along with 150-fold increases in renal MT concentrations, reaching 800 µg MT/g kidney. In MT-null mice, renal Cd concentration (10 µg/g) was much lower, and renal MT was nonexistent. The maximum tolerated dose of Cd in MT-null mice was approximately one-eighth that of controls. MT-null mice were more susceptible than controls to Cd-induced renal injury, as evidenced by increased urinary excretion of protein, glucose, 
-glutamyl-transferase, and N-acetyl-ß-D-glucosaminidase, as well as by increased blood urea nitrogen levels. Kidneys of Cd-treated mice were enlarged and histopathology showed various types of lesions, including proximal tubular degeneration, apoptosis, atrophy, interstitial inflammation, and glomerular swelling. These lesions were more severe in MT-null than in control mice, mirroring the biochemical analyses. These data indicate that Cd-induced renal injury is not necessarily mediated through the CdMT complex and that MT is an important intracellular protein in protecting against chronic Cd nephrotoxicity.
Key Words: cadmium chloride; chronic exposure; nephrotoxicity; proteinuria; glucosuria; enzymuria; blood urea nitrogen; histopathology; metallothionein; CdMT complex; MT-null mice.
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