Protection by Zinc-Metallothionein (ZnMT) against Cadmium-Metallothionein-Induced Nephrotoxicity

Abstract

In contrast to inorganic Cd, acute iv administration of Cd bound to metallothionein (CdMT) concentrates in renal tissue. This uptake of CdMT produces functional and morphological changes in kidneys, similar to those observed after chronic exposure to inorganic Cd. In order to examine the importance of the metal component of MT in the renal uptake of MT, the renal concentration of 35S after administration of [35S]ZnMT and [35S]CdMT was compared. Renal uptake of 35S from both CdMT and ZnMT was very rapid, with peak concentrations observed 15–30 min after administration. 35S in kidneys increased in a dose-dependent manner after administration of various doses of [35S]ZnMT, up to 1.3 μmole MT/kg; however, higher doses did not further increase renal 35S concentrations. A similar saturation of 35S reabsorption was observed for the renal uptake of [35S]CdMT. CdMT produced renal injury with doses as low as 0.26 μmol MT/kg (0.2 mg Cd/kg). In contrast, with a dose of ZnMT as high as 5.12 μmol MT/kg (2 mg Zn/kg), no histopathological changes were observed. Therefore, ZnMT appears to be nontoxic even though ZnMT delivers more MT to the kidney than does CdMT. Because ZnMT and CdMT are apparently handled by the same renal transport mechanism, the effects of ZnMT on 109CdMT renal uptake and nephrotoxicity were determined. One group of mice was given a nephrotoxic dose of 109CdMT (0.51 μmol MT/kg containing 0.4 mg Cd/kg, iv), and the other group received an equimolar dose of unlabeled ZnMT 1 min before 109CdMT administration. Renal function was evaluated by measuring urinary glucose and protein excretion, as well as histopathology. Marked renal toxicity was observed 24 hr after 109CdMT administration. In contrast, renal function appeared normal in mice receiving ZnMT before 109CdMT. However, a similar concentration of 109Cd was found in kidneys of both groups. The present results demonstrate that ZnMT is not only nontoxic to the kidney at a dose as high as 5 μmol MT/kg, but can also protect against the nephrotoxic effect of CdMT without decreasing renal Cd concentration.