Following significant reductions in renal mass (as a result of renal disease, surgery or the aging process) the remaining functional renal tissue undergoes an adaptation known as compensatory renal growth. During this process, the remaining renal mass increases, mainly due to cellular hypertrophy. Although compensatory renal growth is vital to the survival of the organism, it may prove to be detrimental by altering the susceptibility of the remaining functional renal mass to the nephrotoxic effects of certain nephrotoxicants, such as inorganic mercury (Hg). Evidence from animal studies indicates that uninephrectomized animals develop a more severe form of the nephropathy induced by Hg than normal animals with two kidneys. This increased severity appears to be associated with an increase in the accumulation of Hg in the outer stripe of the outer medulla, specifically in the pars recta of the proximal tubule, which is the most vulnerable segment of the nephron to the toxic effects of Hg. The mechanisms responsible for the increased renal accumulation of Hg are unknown. However, possible mechanisms include increased transport of Hg along the proximal tubule, increased delivery of Hg to the proximal tubule as a result of increased renal blood flow and/or glomerular filtration rate, and/or alterations in the metabolism of intracellular ligands that bind Hg.
The aim of this proposal is to define the mechanisms involved in the increased accumulation of Hg in the remnant kidney subsequent to uninephrectomy. Two in vitro models derived from rabbit renal tissue will be used to address this aim: 1) Isolated perfused S2 and S3 segments of the proximal tubule and 2) brush-border and basolateral membrane vesicles. Three primary hypotheses will be tested: 1) Significant reductions of renal mass result in increased activity and expression of luminal and basolateral carrier proteins that transport Hg into proximal tubular epithelial cells; 2) Significant reductions of renal mass result in increased rates of delivery of Hg to the luminal compartment of the proximal tubular epithelium, which in turn causes increased cellular accumulation of Hg; 3) Significant reductions of renal mass result in increased concentrations of thiols in proximal tubular epithelial cells and this is correlated with increased transport and cellular accumulation of Hg. A fourth hypothesis tested shall begin to be tested within the framework of testing the three primary hypotheses. That is, that the increased cellular accumulation of Hg that results from significant reductions of renal mass correlates with increased Hg-Induced cytotoxicity. This project has significant relevance to human health because there is a large population of humans who have reduced renal mass and may be at greater risk of becoming intoxicated by Hg and other nephrotoxicants than normal individuals.
