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ToxSci Advance Access published online on December 15, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi062
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Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Received August 19, 2004
Accepted December 9, 2004

Systems Toxicology

Calcium Oxalate Monohydrate, a Metabolite of Ethylene Glycol, Is Toxic for Rat Renal Mitochondrial Function

Kenneth E. McMartin 1* and Kendall B. Wallace 2

1 Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932
2 Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth, MN 55812

* To whom correspondence should be addressed.
Kenneth E. McMartin, E-mail: kmcmar{at}lsuhsc.edu


  Abstract

Ethylene glycol poisoning can produce acute renal failure, requiring long-term hemodialysis to restore function. The mechanism of the renal failure is unknown, but is associated with tubular cell necrosis and ethylene glycol metabolism. The end metabolite of ethylene glycol is oxalic acid, the precipitation of which as calcium oxalate monohydrate (COM) crystals in the tubular lumen has been linked with the renal toxicity. Our recent studies suggest that COM is an intracellular toxicant to normal human proximal tubule cells in culture. The present studies were designed to assess whether COM or ionic oxalate alters mitochondrial function so as to lead to renal cell death. In isolated rat kidney mitochondria, COM produced a dose-dependent decrease in State 3 respiration (40% decrease at 0.05 mM COM with either succinate or glutamate/malate as substrate), without affecting either State 4 respiration or the ADP/O ratio. COM, from 0.01-0.05 mM also dose-dependently increased mitochondrial swelling, which was completely blocked by cyclosporin A. The inhibition of State 3 respiration, however, was not reversed by cyclosporin A administration. Potassium oxalate, at concentrations up to 5 mM did not inhibit mitochondrial respiration or induce swelling. These results suggest that COM, and not the oxalate ion, damages rat kidney mitochondria and induces the mitochondrial permeability transition, which may then lead to renal cell death. Since COM is transported intracellularly by kidney cells, the renal toxicity of ethylene glycol may result from inhibition of mitochondrial respiratory function in proximal tubular cells by COM crystals.

Keywords: mitochondrial permeability transition; ethylene glycol poisoning; renal toxicity; oxalate crystals.
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