Amelioration of glomerular injury in doxorubicin hydrochloride nephrosis by dimethylthiourea.
The hydroxyl radical scavengers dimethylthiourea (DMTU), sodium benzoate, and dimethylsulfoxide (DMSO) were administered to rats before doxorubicin hydrochloride (ADR) (5 mg/kg, IV) to probe the role of free radicals in mediating proteinuria in doxorubicin hydrochloride nephrosis (AN). Because ADR stimulates free radical production, the role of renal glutathione was also evaluated; glutathione metabolism is involved in tissue detoxification processes. DMTU administration to rats with AN caused a significant (p less than 0.01) reduction in their proteinuria after 7 days (52.84 +/- 13.21 mg/24 hours) when they were compared with ADR controls (155.81 +/- 20.16 mg/24 hours). In similar fashion, their urine albumin excretion was also significantly reduced when compared with that of ADR controls (11.13 +/- 2.75 mg/24 hours vs 32.08 +/- 4.14 mg/24 hours; p less than 0.01). DMTU-treated rats also had significantly (p less than 0.001) reduced urinary protein and albumin excretion at 14 days when compared with rats that received ADR alone. The urinary excretion of lysozyme and N-acetyl-glucosaminidase, markers of renal tubular injury, were significantly increased after 7 or 14 days in rats with AN, despite DMTU treatment. Creatinine clearance was significantly reduced (p less than 0.05) in rats receiving ADR alone (0.223 +/- 0.011 ml/min/100 gm) when compared with that in normal controls (0.331 +/- 0.027 ml/min/100 gm) or DMTU-treated rats (0.289 +/- 0.035 ml/min/100 gm). Unlike DMTU, neither sodium benzoate nor DMSO reduced proteinuria in rats with AN.(ABSTRACT TRUNCATED AT 250 WORDS)
Milner
L S
LS
Department of Pediatrics, University of Nebraska Medical Center, Omaha 68198-2165.
Wei
S H
SH
Houser
M T
MT
D000118:Acetylglucosaminidase / Q000652:urine; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D019817:Benzoic Acid; D003401:Creatine / Q000652:urine; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin; D016166:Free Radical Scavengers; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism / Q000494:pharmacology; D017665:Hydroxyl Radical; D007275:Injections, Intravenous; D007672:Kidney Cortex / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009113:Muramidase / Q000652:urine; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D001565:Benzoates; D016166:Free Radical Scavengers; D006878:Hydroxides; D017665:Hydroxyl Radical; D004317:Doxorubicin; C038983:1,3-dimethylthiourea; D019817:Benzoic Acid; D009113:Muramidase; D000118:Acetylglucosaminidase; D005978:Glutathione; D013890:Thiourea; D003401:Creatine; D004121:Dimethyl Sulfoxide