Antibody-mediated glomerulonephritis in man may be exacerbated by infection and this

Antibody-mediated glomerulonephritis in man may be exacerbated by infection and this effect may be mediated by bacterial endotoxin. and genetic background. In this study we show a synergy between antibody and endotoxin in causing a neutrophil influx. We also show that C1q-deficient mice have an increased susceptibility to glomerular 12-O-tetradecanoyl phorbol-13-acetate inflammation but this is seen only on a mixed 129/Sv × C57BL/6 genetic background. On a C57BL/6 background we did not find any differences in disease susceptibility when wildtype C1q factor B or factor B/C2 deficient mice were compared. We also demonstrate that C57BL/6 mice are more susceptible to glomerular inflammation than 129/Sv mice. These results show that endotoxin is required in this model in mice and that complement does not play a major role in glomerular inflammation in C57BL/6 mice. C1q may play a protective role in mixed-strain 129/Sv × C57BL/6 mice but the data may also be explained by systematic bias in background genes as there is a large difference in disease susceptibility between C57BL/6 and 129/Sv mice. given one hour before injection of nephrotoxic antibody could exacerbate injury as shown by an increased neutrophil influx and 24 h albuminuria [7]. The effect Rabbit Polyclonal to ARNT. of endotoxin-contamination of nephrotoxic antibody batches was reported and a correlation between the degree of endotoxin contamination of different batches of nephrotoxic rabbit antibody and the ability of these batches to induce albuminuria in the rat was found [8]. Heterologous nephrotoxic nephritis has also been established in the mouse [9]. In early studies in mice morphological changes were not observed in the heterologous phase despite the administration 12-O-tetradecanoyl phorbol-13-acetate of doses of antibody much larger than those required to cause heterologous injury in the rat [10]. We hypothesized that one reason that it proved more difficult to establish a reproducible heterologous model in the mouse was that there is a more significant requirement for endotoxin in this species. The studies in rat referred to above [7 8 supported the hypothesis that endotoxin contamination of nephrotoxic antibody exacerbated disease in this model. However the severity of disease caused by antibody with low levels of endotoxin was not directly compared with disease induced by the same antibody with endotoxin added. The role of complement in the model of heterologous nephrotoxic nephritis 12-O-tetradecanoyl phorbol-13-acetate in the mouse is unresolved. In the rat complement-dependence has been shown [6 11 12 This was deduced from experiments 12-O-tetradecanoyl phorbol-13-acetate in which animals were depleted of complement by injections of aggregated human gamma globulin or the complement-fixing ability of the nephrotoxic antibody was decreased by reduction with mercaptoethanol. Initial studies in the B10.D2 and C57BL/10 mice using cobra venom factor did not support a role for complement 12-O-tetradecanoyl phorbol-13-acetate in this species [13 14 A number of investigators have studied the role of complement in heterologous nephrotoxic nephritis in mixed-strain knockout mice. For example two groups found that both the neutrophil influx and proteinuria in this 12-O-tetradecanoyl phorbol-13-acetate model were dependent on the classical pathway [15 16 However in a third study it was reported that the neutrophil influx in C3 and C4 deficient mice was the same as in wild-type mice [17]. Many initial studies of ‘knockout’ mice such as those described above are performed in animals of mixed 129/Sv × C57BL/6 genetic background because these are usually the first animals available for study after the generation of a mouse with a specific targetted deletion. We began by exploring systematically the requirement for endotoxin in a model of antibody-mediated acute nephrotoxic nephritis in the mouse. Our studies on the role of complement started with a comparison of wild-type and C1q-deficient mice on a C57BL/6 × 129/Sv mixed genetic background. We then compared wild-type mice with C1q factor B and factor B/C2 deficient mice on a C57BL/6 background. In addition we compared wild-type mice of 129/Sv and C57BL/6 backgrounds to see if these strains differed significantly in the model of nephrotoxic nephritis. If this was the case it would potentially complicate the.