Chronic kidney disease, which affects approximately 17% of the adult population (about 40,000,000 adults) in the United States, is characterized by a progressive loss of nephrons. Once a significant loss of renal mass occurs, the remaining functioning nephrons undergo compensatory changes, which include increases in renal blood flow and hypertrophy of renal tubular cells. While these changes are vital for survival, they may subject the remaining nephrons to greater levels of nephrotoxicants, one of which is inorganic mercury (Hg2+). Mercury is prevalent in the environment and inorganic forms have serious detrimental effects in the kidney. In fact, the kidney, specifically the proximal tubule, is the primary site of Hg2+ accumulation and toxicity. Proximal tubules are also primary sites of compensatory tubular hypertrophy. We have shown previously that, in models of reduced renal mass, there is a significant change in the disposition of Hg2+ and an increased risk of intoxication by Hg2+. These studies, however, did not identify or examine specific mechanisms responsible for the observed alterations in Hg2+ disposition. Therefore, the purpose of the proposed studies is to assess the effect of compensatory cellular hypertrophy on specific mechanisms involved in the uptake and secretion of Hg2+ in proximal tubules. These studies will focus on the organic anion transporters (OAT) 1 and 3 in the basolateral membrane, and system b0,+, OAT5, and the multidrug resistance-associated proteins (MRP) 2 and 4 in the luminal membrane. These studies will test the hypothesis that compensatory cellular hypertrophy is associated with increased transport of Hg2+ in proximal tubular cells. To test this hypothesis, we propose three specific aims: 1) To test the hypothesis that luminal uptake of select thiol S-conjugates of Hg2+ into PT cells is increased following compensatory cellular hypertrophy;2) To test the hypothesis that basolateral uptake of Hg2+ by hypertrophied PT cells is related to an increase in the uptake of transportable species of Hg2+ by OAT1 and OAT3;3) To test the hypothesis that the luminal export of Hg2+ from PT cells increases following compensatory cellular hypertrophy and is promoted by thiol-containing chelators via one or more multidrug resistance-associated proteins (MRPs). These studies will utilize isolated perfused proximal tubules two animal models of reduced renal mass: 50% nephrectomized (NPX) and 75% NPX rabbits. 50% NPX animals are models of reduced renal mass where compensatory changes maintain normal fluid and electrolyte balance. 75% NPX animals are models of early stages of chronic renal failure wherein fluid and electrolyte balance is altered. These studies are significant in that they will provide new mechanistic data related to the transport of Hg2+ in models of reduced renal mass. Moreover, some of the proposed studies will utilize known chelator of Hg2+, data from these studies will be significant clinically in that they may provide additional information regarding the therapeutic efficacy of using DMPS to treat both normal humans and humans with reduced renal mass that have been exposed to deleterious doses of Hg2+.
Chronic kidney disease affects approximately 17% of the adult population (about 40,000,000 adults) in the United States and is one of the nation's most serious health concerns. In addition, mercury is a prevalent environmental toxicant to which humans are exposed frequently. The proposed studies are significant in that they will provide important information related to the way in which mercury is likely handled and eliminated in patients with significant reductions of functional renal mass.
| Orr, Sarah E; Joshee, Lucy; Barkin, Jennifer et al. (2018) Disposition of methylmercury over time in a 75% nephrectomized rat model. J Toxicol Environ Health A 81:349-360 |
| Oliveira, Cláudia; Joshee, Lucy; Bridges, Christy C (2018) MRP2 and the Transport Kinetics of Cysteine Conjugates of Inorganic Mercury. Biol Trace Elem Res 184:279-286 |
| Orr, Sarah E; Barnes, Mary C; George, Hannah S et al. (2018) Exposure to mixtures of mercury, cadmium, lead, and arsenic alters the disposition of single metals in tissues of Wistar rats. J Toxicol Environ Health A :1-11 |
| Orr, Sarah E; Franklin, Reneé C; George, Hannah S et al. (2018) Pregnancy Alters Renal and Blood Burden of Mercury in Females. Biol Trace Elem Res 186:9-11 |
| Orr, Sarah E; Bridges, Christy C (2017) Chronic Kidney Disease and Exposure to Nephrotoxic Metals. Int J Mol Sci 18: |
| Oliveira, Cláudia; Joshee, Lucy; George, Hannah et al. (2017) Oral exposure of pregnant rats to toxic doses of methylmercury alters fetal accumulation. Reprod Toxicol 69:265-275 |
| Bridges, Christy C; Zalups, Rudolfs K (2017) Mechanisms involved in the transport of mercuric ions in target tissues. Arch Toxicol 91:63-81 |
| Bridges, Christy C; Zalups, Rudolfs K (2017) The aging kidney and the nephrotoxic effects of mercury. J Toxicol Environ Health B Crit Rev 20:55-80 |
| Oliveira, Cláudia S; Joshee, Lucy; Zalups, Rudolfs K et al. (2016) Compensatory renal hypertrophy and the handling of an acute nephrotoxicant in a model of aging. Exp Gerontol 75:16-23 |
| Bridges, Christy C; Barfuss, Delon W; Joshee, Lucy et al. (2016) Compensatory Renal Hypertrophy and the Uptake of Cysteine S-Conjugates of Hg2+ in Isolated S2 Proximal Tubular Segments. Toxicol Sci 154:278-288 |
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