Effects of divalent metals on the isolated rat glomerulus

Glomerular changes are prominent in metal-induced nephrotoxicity, and the glomerulus may be a primary site of damage in some cases. In order to separate direct effects of metal ions from those occurring secondary to systemic or post-glomerular toxicity, we have studied the effects of divalent salts of Hg, Cd, Cu, Zn, Mn, Ni and Co on several metabolic parameters in freshly isolated rat glomeruli. The concentration of the metal ion causing a 50% reduction in the incorporation of [3H]leucine into protein over 16 h varied from 30 microM with Cd to about 2 mM with Ni and Mn. The log of the concentration was significantly correlated with the softness of the metal ion, indicating greater toxicity of ions such as Cd2+ and Hg2+ that prefer sulphur as a ligand. Incorporation of [3H]sulphate into proteoglycans was affected in a comparable manner to total protein synthesis. However, the softer metals caused a preferential decrease in the production of more highly charged dermatan sulphate, indicative of an effect on mesangial cells. Glomeruli were found to contain about 50 fmol each of glutathione upon isolation, and this value decreased with time. However, Cd and Zn caused increases in total glomerular glutathione, and this phenomenon was inhibited by buthionine sulphoximine, indicating that synthesis of new glutathione was responsible for the increases. These studies demonstrate the usefulness of the isolated glomerulus for investigating mechanisms of nephrotoxicity, and indicate that the mesangial cell may be a preferred target for some metal ions.