METALLOTHIONEIN-I-TRANSGENIC MICE ARE NOT PROTECTED FROM ACUTE CADMIUM-METALLOTHIONEIN-INDUCED NEPHROTOXICITY

Mice pretreated with Zn have increased renal metallothionein (MT) leve ls and are protected from CdMT nephrotoxicity. To determine whether MT is important in this Zn-induced protection against CdMT-induced nephr otoxicity, MT-transgenic mice that have high levels of MT in their kid neys (10-fold over control mice) have been studied to determine whethe r they are resistant to CdMT-induced nephrotoxicity. Mice were injecte d 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 mi ce. However, similar increases in protein and glucose excretion were a lso observed in MT-transgenic mice, CdMT also induced a similar dose-d ependent proximal tubular cell necrosis in both control and MT-transge nic mice in a dose-dependent manner. Treatment of control mice with Zn (100 mu mol/kg, sc x 2 days) increased renal MT to levels similar to those of untreated MT-transgenic mice and protected against CdMT-induc ed renal injury. Furthermore, when Zn (25-100 mu mol/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 appea r to be due to induction of renal MT. (C) 1996 Academic Press, Inc.