Metallothionein-I-transgenic mice are not protected from acute cadmium-metallothionein-induced nephrotoxicity.
Mice pretreated with Zn have increased renal metallothionein (MT) levels and are protected from CdMT nephrotoxicity. To determine whether MT is important in this Zn-induced protection against CdMT-induced nephrotoxicity, MT-transgenic mice that have high levels of MT in their kidneys (10-fold over control mice) have been studied to determine whether they are resistant to CdMT-induced nephrotoxicity. Mice were injected with CdMT (0.1-0.6 mg Cd/kg, iv) and kidney injury was evaluated 24 hr later. CdMT produced renal toxicity in a dose-dependent manner. At a nephrotoxic dose of CdMT (0.4 mg Cd/kg), urinary protein and glucose excretion were increased 30- and 60-fold, respectively, in control mice. However, similar increases in protein and glucose excretion were also observed in MT-transgenic mice. CdMT also induced a similar dose-dependent proximal tubular cell necrosis in both control and MT-transgenic mice in a dose-dependent manner. Treatment of control mice with Zn (100 micromol/kg, sc x 2 days) increased renal MT to levels similar to those of untreated MT-transgenic mice and protected against CdMT-induced renal injury. Furthermore, when Zn (25-100 micromol/kg, sc) was given immediately before CdMT injection (i.e., without preinduction of MT), it was still effective in preventing CdMT nephrotoxicity. We conclude that Zn-induced protection against CdMT nephrotoxicity does not appear to be due to induction of renal MT.
Liu
Y P
YP
Department of Pharmacology, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Liu
J
J
Palmiter
R D
RD
Klaassen
C D
CD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006029:Glycosuria / Q000652:urine; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011507:Proteinuria / Q000652:urine
C004203:cadmium-binding protein; D008668:Metallothionein