thiourea and Albuminuria

Focal segmental glomerulosclerosis is a steroid-resistant glomerular disease characterized by foot process flattening and heavy proteinuria. A similar disease was found to occur spontaneously in mice in which the Mpv17 gene was inactivated by retroviral insertion (Mpv17-/- mice). Here evidence is provided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that were found in isolated glomeruli of Mpv17-/- mice. The development of glomerular disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid treatment. Although the glomerular polyanion was greatly reduced in proteinuric Mpv17-/- mice, it was preserved by antioxidative therapy. These results indicate that the glomerular disease in Mpv17-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experimental therapies with scavengers of oxygen radicals and lipid peroxidation efficiently ameliorate glomerular damage.

Topics: Aging; Albuminuria; Animals; Disease Models, Animal; Free Radical Scavengers; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Kidney Glomerulus; Lipid Peroxidation; Lipid Peroxides; Membrane Proteins; Methylprednisolone; Mice; Mice, Inbred BALB C; Mice, Knockout; Probucol; Proteins; Proteinuria; Reactive Oxygen Species; Sialoglycoproteins; Superoxides; Thiourea

We evaluated the roles of reactive oxygen species and intrinsic antioxidant enzymes in the development of daunomycin (DM)-induced nephropathy in mice. A single dose of DM (20 mg/kg intravenously) induced proteinuria by day 7 and the nephrotic syndrome by day 14 in DM-sensitive strain (A/J) but not in DM-resistant strain (C57BL/6J) (B6). Renal cortical lipid peroxide levels in the A/J mice significantly increased at days 2, 4, and 7 after DM injection, whereas no increase was observed in the B6 mice. The resistance to DM in B6 mice was associated with higher activities in renal cortical superoxide dismutase and glutathione peroxidase. The administration of superoxide dismutase or of dimethylthiourea significantly suppressed the DM-induced proteinuria in the A/J mice. Four days of superoxide dismutase or dimethylthiourea administration suppressed the proteinuria. These findings suggested that murine DM-nephropathy appeared to be mediated by reactive oxygen species and that intrinsic antioxidant enzyme activities may play an important role in the susceptibility to DM-induced nephropathy in mice.

Topics: Albuminuria; Animals; Catalase; Daunorubicin; Free Radical Scavengers; Glutathione; Glutathione Peroxidase; Kidney; Kidney Diseases; Lipid Peroxides; Male; Mice; Mice, Inbred Strains; Nephrotic Syndrome; Reactive Oxygen Species; Serum Albumin; Superoxide Dismutase; Thiourea

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)

Topics: Acetylglucosaminidase; Albuminuria; Animals; Benzoates; Benzoic Acid; Creatine; Dimethyl Sulfoxide; Disease Models, Animal; Doxorubicin; Free Radical Scavengers; Glomerular Filtration Rate; Glutathione; Hydroxides; Hydroxyl Radical; Injections, Intravenous; Kidney Cortex; Male; Muramidase; Nephrosis; Proteinuria; Rats; Rats, Inbred Strains; Thiourea