Reactive oxygen metabolites in toxic acute renal failure.
We have examined the role of reactive oxygen metabolites (ROM) in gentamicin nephrotoxicity and in glycerol-induced acute renal failure, a model for myoglobinuric acute renal failure. Several agents which affect mitochondrial respiration have been shown to enhance the generation of hydrogen peroxide. Based on gentamicin's ability to alter mitochondrial respiration both in vitro and in vivo we postulated that gentamicin may enhance the generation of ROM by renal cortical mitochondria. Gentamicin, in a dose-dependent fashion, enhanced hydrogen peroxide production by rat renal cortical mitochondria as measured by the decrease in scopoletin fluorescence. At the highest concentration of gentamicin tested (4.0 mM), the rate of hydrogen peroxide generation was markedly increased from 0.17 +/- 0.02 to 6.21 +/- 0.67 nmol/mg/min. We next demonstrated that hydroxyl radical scavengers and an iron chelator provide a marked functional and histological protection in gentamicin-induced acute renal failure in rats. Hydroxyl radical scavengers and the iron chelator deferoxamine also protected renal function in glycerol-injected rats, a model for acute renal failure due to muscle injury. Although these data suggest that ROM may be important mediators of toxic renal injury, in vivo generation of ROM by kidney in normal and pathological states has not been previously examined. Aminotriazole (AT) irreversibly inactivates catalase only in the presence of hydrogen peroxide and previous studies have shown that AT-mediated inhibition of catalase in a sensitive measure of in vivo changes in the hydrogen peroxide generation. Using this method, we have demonstrated the in vivo generation of hydrogen peroxide under normal conditions and enhanced generation of hydrogen peroxide in rats treated with gentamicin or glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)
Shah
S V
SV
Department of Medicine, University of Arkansas for Medical Sciences, Little Rock 72205.
Walker
P D
PD
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D005609:Free Radicals; D005839:Gentamicins / Q000009:adverse effects*; D005990:Glycerol / Q000009:adverse effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects*; D006878:Hydroxides / Q000009:adverse effects; D017665:Hydroxyl Radical; D007501:Iron / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009212:Myoglobinuria / Q000150:complications; D051381:Rats
D005609:Free Radicals; D005839:Gentamicins; D006878:Hydroxides; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron; D005990:Glycerol; D002118:Calcium