Calcium oxalate monohydrate, a metabolite of ethylene glycol, is toxic for rat renal mitochondrial function.
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.
McMartin
Kenneth E
KE
Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130-3932, USA. kmcmar@lsuhsc.edu
Wallace
Kendall B
KB
D000818:Animals; D002129:Calcium Oxalate / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D019855:Ethylene Glycol / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D007166:Immunosuppressive Agents; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000378:metabolism
D007166:Immunosuppressive Agents; D008293:Malates; D013386:Succinates; D002129:Calcium Oxalate; D018698:Glutamic Acid; D016572:Cyclosporine; D019855:Ethylene Glycol