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Grantee Research Project Results

Grantee Research Project Results

The Mechanism of Cadmium Nephrotoxicity

EPA Grant Number: U915642
Title: The Mechanism of Cadmium Nephrotoxicity
Investigators: Tang, Weifeng
Institution: University of Rhode Island
EPA Project Officer: Just, Theodore J.
Project Period: September 1, 1999 through August 1, 2002
Project Amount: $26,882
RFA: STAR Graduate Fellowships (1999)
Research Category: Fellowship - Toxicology , Academic Fellowships , Health Effects

Description:

Objective:

The objective of this research project is to demonstrate that: (1) renal mitochondrial damage on cadmium-metallothionein (CdMT) administration is caused by Cd++, and (2) mitochondria are the critical executioner of Cd-induced apoptosis in the kidney. The mechanism underlying chronic cadmium (Cd) nephrotoxicity remains to be understood.

Approach:

It is generally understood that chronic Cd-induced nephrotoxicity is caused by CdMT that is synthesized in and transferred from the liver. Thus, acute CdMT injection has been used extensively to study the mechanism of Cd-induced nephrotoxicity. Rats will be injected intraperitoneally with 0.3 mg Cd as CdMT/kg. After 6, 8, and 12 hours of CdMT injection, six animals/group will be sacrificed. Renal cortical mitochondria will be isolated and mitochondrial respiratory function will be analyzed. For in vitro study, renal cortical mitochondria isolated from untreated rats will be incubated with 0.1-2 µM Cd as CdCl2 at 25°C for 1 minute followed by measurement of mitochondrial respiratory functions. To study the role of mitochondria in Cd-induced apoptosis, LLC-PK1 cells will be treated with 20 µM CdCl2 for 5 hours. At the end of Cd exposure, the cells will be washed and cultured for up to 12 hours. Mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation will be analyzed. In some cases, the cells will be cotreated with a caspase-3 inhibitor or mitochondrial membrane permeability transition pores blocker.

Supplemental Keywords:

fellowship, cadmium, Cd, nephrotoxicity, mitochondria, apoptosis, cadmium-metallothionein, CdMT, liver, renal, DNA fragmentation, toxicology., Health, Scientific Discipline, PHYSICAL ASPECTS, Health Risk Assessment, Risk Assessments, Biochemistry, Physical Processes, toxicology, renal mitrochondrial damage, exposure, nephrotoxicity, human exposure, renal damage, kidney function, immunotoxicology, apoptosis, cadmium, human health risk

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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