Toxicological Sciences, Vol 50, 221-227, Copyright © 1999 by Society of Toxicology
Y Liu, J Liu, SS Habeebu and CD Klaassen
Metallothionein (MT) is a low-molecular-weight, cysteine-rich, metal-
binding protein. Induction of MT has been proposed to be an important
adaptive mechanism in decreasing Cd toxicity. MT has been shown to protect
against CdCl2-induced lethality and hepatotoxicity; however, MT does not
protect against acute CdMT-induced nephrotoxicity. This study was aimed at
clarifying the role of metallothionein in chronic CdMT- induced renal
injury. Wild type and MT-I/II knockout (MT-null) mice were therefore given
sc injections of CdMT (25 and 100 microg Cd/kg) or saline daily, 6
times/week for 6 weeks, and renal injury was evaluated. Multiple injections
of CdMT to wild-type mice resulted in renal Cd concentrations up to 120
microg/g kidney, along with a 100-fold increase in renal MT (450 microg/g
kidney). In contrast, renal Cd concentration in MT-null mice administered
multiple injections of CdMT reached a much lower level than in wild-type
mice (<10 microg/g kidney). Although less Cd accumulated in their
kidneys, MT-null mice were more susceptible than wild-type mice to
CdMT-induced nephrotoxicity, as indicated by increased urinary excretion of
protein and N-acetyl-beta-D-glucosaminidase, as well as by elevated blood
urea nitrogen levels. At the higher daily dose of CdMT (100 microg Cd/kg),
kidneys of MT-null mice were enlarged. Chronic CdMT administration
eventually damaged the entire kidney, which included glomerular swelling,
interstitial inflammation, edema, tubular cell degeneration, and atrophy.
In contrast to a single injection of CdMT that produces proximal tubular
necrosis, chronic injection of CdMT results in tubular cell apoptosis in
both wild-type and MT-null mice. These data indicate that chronic CdMT
administration produces similar renal injury to that observed after chronic
CdCl2 administration, and that intracellular MT protects against
nephrotoxicity produced by chronic CdMT administration.
ARTICLES
Metallothionein protects against the nephrotoxicity produced by chronic CdMT exposure
Center for Environmental Health and Occupational Medicine, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
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