When renal mass is reduced significantly in humans and other mammals, as a result of renal disease, surgery or the aging process, the remaining renal tissue undergoes an adaptation known as compensatory renal growth. During compensatory renal growth, the mass of the remaining renal tissue increases, primarily as a consequence of cellular hypertrophy in certain segments of the nephron. In association with this cellular hypertrophy, there is increased transport of water and electrolytes, increased renal cellular metabolism and increased renal blood and plasma flow and single nephron glomerular filtration rate. Although these changes are vital to the survival of the organism, they may alter the susceptibility of the organism to the nephrotoxic effects of certain nephrotoxicants, such as inorganic mercury (Hg). Evidence from animal studies indicate that nephrectomized animals develop a more severe form of the nephropathy induced by inorganic Hg than normal animals with two kidneys. The increase in the severity of the nephropathy appears to be associated with an increase in 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 inorganic mercury. The increased accumulation of Hg that occurs after renal mass is reduced could be due to 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 binding ligands for Hg in the remaining renal mass. Current evidence indicates that as a result of compensatory renal growth there are increases in the renal concentration and content of the intracellular thiols glutathione (GSH) and metallothionein (MT), especially in the renal cortex and outer stripe of the outer medulla. Both GSH and MT are potential binding ligands for mercury. One of the principal aims of the present proposal is to evaluate in rats the effect of uninephrectomy on the uptake and subcellular distribution of Hg in the renal Cortex and outer stripe of the outer medulla. As part of this aim, we will evaluate the influence of altering the intracellular concentration of GSH and MT on the uptake and subcellular distribution of Hg. We will also determine if the rates of transport of Hg into luminal and basolateral membrane vesicles isolated from the renal cortex and outer medulla are enhanced as a result of compensatory renal cellular hypertrophy. The second major objective of this proposal is to evaluate the role of both intracellular (GSH and MT) and extracellular (GSH, cysteine and albumin) thiol-containing ligands on the accumulation and toxicity of Hg in proximal tubular epithelial cells of the rat using whole animal metabolic studies and suspensions of isolated proximal tubular cells. The third and final objective of this proposal is to begin investigating, both in vivo and in vitro, the effects of 75% nephrectomy, which is a model of early stages of chronic renal failure, on the renal (specifically proximal tubular) accumulation of mercury and the nephropathy induced by low doses of inorganic Hg. These studies may have significant relevance to human health since there is a larger population of humans who have reduced renal mass and may be at greater risk of becoming intoxicated by Hg than normal individuals.
