Mercury is a group IIB transition metal that is widely disseminated environmental and occupational hazard in many places of the United States (and other countries). One of the primary target sites for the accumulation and toxicity of mercury is the kidney. The various forms of mercury tend to accumulate mainly along the three segments of the proximal tubule, although distal segments of the nephron may be involved in some aspect of the renal handling of mercury. Based on data from our previous application, inorganic mercury appears to be taken up along the three segments of the proximal tubule in a heterogeneous manner. Moreover, at least two distinct mechanisms are involved in the uptake of mercury along the proximal tubule. One of these mechanisms is localized on the luminal membrane of the proximal tubular epithelial cells and the other is localized on the basolateral membrane. The overall aim of this project is to determine the specific mechanisms involved in both the luminal and basolateral uptake of inorganic and organic forms of mercury along the nephron using the isolated perfused tubule technique. Particular focus will be placed on the roles that the enzyme gamma- glutamyltransferase and the organic anion transport system play in the uptake of mercuric ions at the luminal and basolateral membranes, respectively. The investigators have found that these components are involved in some way in the proximal tubular uptake of mercury. The investigator will also characterize the potential uptake and transport of mercury alone distal segments of the nephron, such as in cortical collecting ducts and segments of the ascending thick limbs of the loop of Henle. The isolated perfused tubule technique, is deemed the best in vitro system suited for these types of studies. By better understanding the precise mechanisms by which mercuric ions are handled by the various renal epithelial cells, the investigators will be better able to determine mechanisms involved in the renal toxicity of mercury, and will be better equipped to find more effective ways to prevent and treat renal injury by mercury after environmental or occupational exposure.
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