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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES005980-05A1
Application #
2666186
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (01))
Program Officer
Scherbenske, M James
Project Start
1993-06-01
Project End
2001-07-31
Budget Start
1998-08-05
Budget End
1999-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mercer University Macon
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
065365041
City
Macon
State
GA
Country
United States
Zip Code
31207
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; 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
Zalups, Rudolfs K; Bridges, Christy C (2012) Relationships between the renal handling of DMPS and DMSA and the renal handling of mercury. Chem Res Toxicol 25:1825-38
Wang, Yanhua; Zalups, Rudolfs K; Barfuss, Delon W (2012) Luminal transport of thiol S-conjugates of methylmercury in isolated perfused rabbit renal proximal tubules. Toxicol Lett 213:203-10
Bridges, Christy C; Krasnikov, Boris F; Joshee, Lucy et al. (2012) New insights into the metabolism of organomercury compounds: mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine ?-lyase. Arch Biochem Biophys 517:20-9
Bridges, Christy C; Joshee, Lucy; Zalups, Rudolfs K (2011) MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury. Toxicol Appl Pharmacol 251:50-8
Wang, Yanhua; Zalups, Rudolfs K; Barfuss, Delon W (2010) Potential mechanisms involved in the absorptive transport of cadmium in isolated perfused rabbit renal proximal tubules. Toxicol Lett 193:61-8
Zalups, Rudolfs K; Bridges, Christy C (2010) Seventy-five percent nephrectomy and the disposition of inorganic mercury in 2,3-dimercaptopropanesulfonic acid-treated rats lacking functional multidrug-resistance protein 2. J Pharmacol Exp Ther 332:866-75
Bridges, Christy C; Zalups, Rudolfs K (2010) Transport of inorganic mercury and methylmercury in target tissues and organs. J Toxicol Environ Health B Crit Rev 13:385-410
Zalups, Rudolfs K; Bridges, Christy C (2009) MRP2 involvement in renal proximal tubular elimination of methylmercury mediated by DMPS or DMSA. Toxicol Appl Pharmacol 235:10-7

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