Understanding renal toxicity of heavy metals.

The mechanisms by which metals induce renal injury are, in general, poorly understood. Characteristic features of metal nephrotoxicity are lesions that tend to predominate in specific regions of the nephron within specific cell types. This suggests that certain regions of the nephron are selectively sensitive to specific metals. Regional variability in sensitivity could result from the localization of molecular targets in certain cell populations and/or the localization of transport and binding ligands that deliver metals to targets within the nephron. Significant progress has been made in identifying various extracellular, membrane, and intracellular ligands that are important in the expression of the nephrotoxicity of metals. As an example, mercuric chloride induces a nephropathy that, at the lowest effective doses, is restricted primarily to the S3 segment of the proximal tubule, with involvement of the S2 and S1 segments at higher doses. This specificity appears to be derived, at least in part, from the distribution of enzymes and transport proteins important for the uptake of mercury into proximal tubule cells: apical gamma-glutamyltranspeptidase and the basolateral organic anion transport system. Regional distributions of transport mechanisms for binding proteins appear to be important in the expression of nephrotoxicity of metals. These and other new research developments are reviewed.