Subcellular targets of cadmium nephrotoxicity: cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis

Nephrotoxic effects of cadmium exposure are well established in humans and experimental animals. An early manifestation of such toxicity is calciuria a few hours after injection of CdMT in rats. Protection against calciuria and other adverse effects such as proteinuria (occurring later) is offered by pretreatment with Cd, which effectively induces metallothionein synthesis. In the present experiment, one group of animals was given pretreatment with CdCl2 to induce metallothionein synthesis. The comparison group was left without pretreatment. The distribution of Cd from a normally nephrotoxic dose of 109CdMT was studied by gel chromatography in subcellular fractions of kidney cortex in both groups. In the pretreated animals, 109Cd in the plasma membrane and microsome fractions of renal cortical cells was mainly bound to metallothionein and other low molecular weight proteins at 4 hr. In nonpretreated animals the major part of 109Cd was bound to high molecular weight proteins. These findings indicate that membrane proteins may be important targets for Cd when inducing nephrotoxicity and that sequestering of Cd by metallothionein (and other low molecular weight proteins) may be a mechanism of protection.