Evaluation of the role of reactive oxygen species in doxorubicin hydrochloride nephrosis.
In subcellular systems, doxorubicin hydrochloride (ADR) leads to the generation of reactive oxygen species such as superoxide anion. Because reactive oxygen species have been shown to be important mediators of glomerular injury in several animal models, we sought to determine whether reactive oxygen species play a significant role in the pathogenesis of ADR-induced nephrotic syndrome in the rat. Rats pretreated with a variety of free radical scavengers (superoxide dismutase conjugated to polyethylene glycol [PEGSOD], catalase, catalase plus PEGSOD, dimethylsulfoxide, desferoxamine, or n-acetyl cysteine) had no significant reduction in proteinuria at 3 weeks after ADR administration when compared with rats receiving ADR in the absence of scavengers. No evidence was seen of increased lipid peroxidation or depletion of reduced glutathione in renal cortex tissue obtained up to 24 hours after administration of ADR. No changes were seen in the renal cortical levels of either enzyme activity or immunoreactive protein for the endogenous antioxidant enzymes superoxide dismutase (either the Mn or CuZn forms) or catalase after ADR. Total and MnSOD activities in glomeruli isolated from rats after ADR administration fell significantly, though CuZnSOD activity was increased. The effect of ADR on cultured rat mesangial or epithelial cells was also evaluated. ADR inhibited growth of both cell types at concentrations of approximately 5 to 10 mumol/L, an order of magnitude below the reported Michaelis-Menten constant for ADR-induced superoxide production. The growth inhibitory effect could not be prevented in either cell type by treatment with PEGSOD, catalase, or PEGSOD plus catalase. This combination of results from in vivo and in vitro studies provides no evidence for an important role of reactive oxygen species in ADR nephrosis and suggests that other known mechanisms of ADR cytotoxicity, such as interference with DNA metabolism, mediate the glomerular injury.
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City.
J A
JA
Bertolatus
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Klinzman
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DA
Bronsema
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Ridnour
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Oberley
D000818:Animals; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D016166:Free Radical Scavengers; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D007672:Kidney Cortex / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D010100:Oxygen / Q000378:metabolism / Q000502:physiology*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D011092:Polyethylene Glycols / Q000378:metabolism / Q000494:pharmacology; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology
D016166:Free Radical Scavengers; D011092:Polyethylene Glycols; D008315:Malondialdehyde; D004317:Doxorubicin; D002374:Catalase; D013482:Superoxide Dismutase; D013917:Thrombin; D005978:Glutathione; D010100:Oxygen; D004121:Dimethyl Sulfoxide