Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis

Background: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model. Methods: ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups. Results: The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation. Conclusions: These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model

Generation of B220(low) B cells and production of autoantibodies in mice with experimental amyloidosis: association of primordial T cells with this phenomenon

To investigate the immunological state in amyloidosis, mice were twice intraperitoneally injected (2-week interval) with casein emulsified in complete Freund's adjuvant. Two weeks after the treatment, amyloid deposits were detected in the spleen and other organs of these mice. The number of lymphocytes yielded by the liver and spleen increased significantly. The most affected lymphocyte subset was found to be B cells, namely, the total number of B cells increased and unusual B220(low) B cells were newly generated in the liver and spleen. In other words, not only normal B220(high) B cells but also unusual B220(low) B cells were detected in these organs of mice with amyloidosis. In parallel with this phenomenon, autoantibodies against denatured DNA were detected in sera. Since such autoantibodies are known to accompany the functional activation of NKT cells, NKT cell-deficient mice were used for the induction of amyloidosis. Such mice showed less formation of amyloidosis and lower levels of autoantibodies in sera. Athymic nude mice were NKT cell-deficient but NK1·1(−)TCR(int) cells were present. These athymic mice showed an intermediate induction of amyloidosis. The cytokine profile seen in mice with amyloidosis was the Th0 type, showing simultaneous production of IL-4 and IFNγ. These results suggest that the generation of B220(low) B cells and the production of autoantibodies in aid of primordial T cells may be major immunological mechanisms in amyloidosis mice