In recent decades, environmental levels of the heavy metal, cadmium (Cd), heave steadily risen to potentially toxic levels. Most frequently, chronic exposure to Cd is typically manifested as proteinuria, aminoaciduria and glucosuria clear indicators of nephrotoxicity. Damage occurs in epithelial cells of renal proximal tubules via a receptor mediated uptake of a protein-heavy metal complex. The protein that sequestered Cd and protects against toxicity is metallothionein. Evidence now suggests that the metallothionein-Cd complex receptor in the kidney is a giant glycoprotein receptor known as cubilin (cubilin). The purpose of this application is to confirm these preliminary lines of evidence by elucidating the binding mechanism of entry into the kidney, for heavy metals. We propose to treat normal mice and RAP knockout mice, which lack surface cubilin, with cadmium chloride at subchronic and acute levels to determine mechanisms of toxicity. Isolation and purification of brush border membrane vesicles for studies on peptide interference with MT-heavy metal binding to cubilin will identify competing ligands. Definition of the exact sites at which cadmium-metallothionein binds the renal receptor cubilin should allow the development of protective agents for the whole body accumulation and nephrotoxicity of cadmium. Our working hypothesis is that identification of peptide sites at which cubilin binds metallothionein and MT-bound heavy metals will allow the design of agents protective for heavy metal-induced clinical nephrotoxicity. Our working hypothesis is that identification of peptide sites at which cubilin binds metallothionein and MT-bound heavy metals will allow the design of agents protective for heavy metal-induced clinical nephrotoxicity.
The specific aims of the current proposal are: I. Proximal tubule: to design protective agents for renal proximal tubule heavy metal clinical toxicity. II. To test the protective effects of peptides/proteins interfering with cubilin in animal models of nephrotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Minority Biomedical Research Support Thematic Project Grants (S11)
Project #
5S11ES009996-04
Application #
6644961
Study Section
Special Emphasis Panel (ZES1)
Project Start
2002-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Xavier University of Louisiana
Department
Type
DUNS #
020857876
City
New Orleans
State
LA
Country
United States
Zip Code
70125
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