Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect

Background. The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. Methods. A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w. : GA (15 heterozygous nu/O mice with normal immune system) ; GB (15 homozygous nu/nu athymic mice) ; GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gml antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF-α excretion were measured. Results. After 14 days the proteinuria was 43.8± 1.7 μg/min in GA, 30.2±2.9 μg/min in GB (P< 0.05) and 12.2±2.8 μg/min in GC (GA vs GC, P<0.0001 ; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNF-α urinary excretion was significantly higher in GA (17.3±3.2 mU/min) than in GB (5±0.6 mU/min, P<0.001) and GC (3.2±0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF-α and protein losses (r 2 =0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-α, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. Conclusions. Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-α could be envisaged.