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.
| Cohn, William B; Jones, Richard A; Valverde, Roldan A et al. (2010) Molecular cloning and regulation of mRNA expression of the thyrotropin ? and glycoprotein hormone ? subunits in red drum, Sciaenops ocellatus. Fish Physiol Biochem 36:1277-90 |
| Kale, Shubha P; Carmichael, Mary C; Harris, Kelley et al. (2006) The L1 retrotranspositional stimulation by particulate and soluble cadmium exposure is independent of the generation of DNA breaks. Int J Environ Res Public Health 3:121-8 |
| Gonzalez-Villalobos, Romer; Klassen, R Bryan; Allen, Patricia L et al. (2006) Megalin binds and internalizes angiotensin-(1-7). Am J Physiol Renal Physiol 290:F1270-5 |
| Kale, Shubha P; Moore, Lakisha; Deininger, Prescott L et al. (2005) Heavy metals stimulate human LINE-1 retrotransposition. Int J Environ Res Public Health 2:14-23 |
| Gonzalez-Villalobos, Romer; Klassen, R Bryan; Allen, Patricia L et al. (2005) Megalin binds and internalizes angiotensin II. Am J Physiol Renal Physiol 288:F420-7 |
| El-Sawy, Mohammed; Kale, Shubha P; Dugan, Christine et al. (2005) Nickel stimulates L1 retrotransposition by a post-transcriptional mechanism. J Mol Biol 354:246-57 |
| D'Elia, Riccardo; Allen, Patricia L; Johanson, Kelly et al. (2005) Homozygous diploid deletion strains of Saccharomyces cerevisiae that determine lag phase and dehydration tolerance. Appl Microbiol Biotechnol 67:816-26 |
| Roy-Engel, A M; El-Sawy, M; Farooq, L et al. (2005) Human retroelements may introduce intragenic polyadenylation signals. Cytogenet Genome Res 110:365-71 |
| Klassen, R Bryan S; Allen, Patricia L; Batuman, Vecihi et al. (2005) Light chains are a ligand for megalin. J Appl Physiol 98:257-63 |
| Klassen, R Bryan; Crenshaw, Kimberly; Kozyraki, Renata et al. (2004) Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol 287:F393-403 |
Showing the most recent 10 out of 14 publications
