Mercury is a group IIB transition metal that is a significant environmental and occupational contaminant and hazard in the United States (and other countries). One of the primary target sites where mercuric ions accumulate and induce significant toxic effects is in the kidney. Within the kidneys, mercuric ions accumulate mainly along the three segments of the proximal tubule, although distal segments of the nephron have not been excluded as secondary targets where mercuric ions may be handled. Inorganic mercury appears to be taken up along the three segments of the proximal tubule in a heterogeneous manner. Moreover, at least two distinct sets of mechanisms are involved in the uptake of mercury along the proximal tubule. One of these sets of mechanisms is localized on the luminal membrane and the other is localized on the basolateral membrane. Based on the research we have carried out to date, we have come up with the following central hypothesis: Mercuric conjugates of biologically relevant endogenous thiol-containing molecules (or their metabolites), are 1) the primary transportable species of inorganic mercury in the kidneys, and 2) are taken up by proximal tubular epithelial cells at both the luminal and basolateral membranes by known transporters of other molecules, such as those involved in the transport of amino acids and organic anions, presumably through mechanisms involving molecular homology or """"""""mimicry' One technology we will use to test this hypothesis will include the in vitro stable transfection of a distal-tubular, renal-epithelial, cell-line with the genetic code(s) for specific luminal and basolateral transporters presumed to be involved in the transport of mercury. Expression of a transporter in a cell that normally does contain it will permit us to determine if there is a gain of function. More specifically, we will be able to document if transport (and inhibition of transport) of specific mercuric conjugates occurs. The other technology we propose to use is the isolated perfused tubule, which is the only in vitro technique that allows one to access, perfuse, and bathe virtually any intact segment of the nephron to study the characteristics of particular transport systems under biophysical conditions similar to those found in vivo. With these techniques, we will be able to provide the most detailed and comprehensive assessment, to date, of the mechanisms involved in the uptake of inorganic mercuric ions along pars recta segments of the proximal tubule, which are the segments of the nephron most vulnerable to the nephrotoxic effects of mercury
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