SUMMARY:Decay-accelerating factor (DAF or CD55) is one of a set of regulators that function to protect self cells from deposition of autologous C3b on their surfaces. Its relative importance in vivo, however, is incompletely understood. As one approach to address this issue, we induced nephrotoxic serum (NTS) nephritis in wild-type mice and Daf1 gene-floxed mice devoid of renal DAF expression. For these experiments NTS IgG was administered at a dose (0.5 mg iv) that requires complement for glomerular injury. After 18 hours, renal injury was assessed by proteinuria and by histologic, immunohistochemical, and electron microscopic analyses of kidneys. Fifteen normal and 15 DAF-deficient mice were studied. Baseline albuminuria in the Daf1 Ϫ/Ϫ mice was 115.9 Ϯ 41.4 g/mg creatinine as compared with 85.7 Ϯ 32.3 g/mg creatinine in their Daf1 ϩ/ϩ littermates (p ϭ 0.075). After administration of NTS IgG, albuminuria increased to 2001.7 Ϯ 688.7 g/mg creatinine as compared with 799.7 Ϯ 340.5 g/mg creatinine in the controls (p ϭ 0.0003). Glomerular histology was similar in Daf1 Ϫ/Ϫ and Daf1 ϩ/ϩ mice, with essentially no infiltrating leukocytes. In contrast, electron microscopy revealed severe podocyte fusion in the Daf1 Ϫ/Ϫ mice but only mild focal changes in the controls. Immunohistochemical staining showed equivalent deposition of the administered (sheep) NTS IgG in the Daf1 Ϫ/Ϫ and Daf1 ϩ/ϩ animals. This contrasted with marked deposition of autologous murine C3 in the former and minimal deposition in the latter. The results show that DAF is essential physiologically for protecting glomeruli against autologous complement attack initiated by the classical pathway. (Lab Invest 2002, 82:563-569).D ifferent forms of nephrotoxic serum (NTS)-induced nephritis in rats and mice have been widely utilized as animal models for human antibodyinduced renal diseases (reviewed in Salant and Cybulsky, 1988). The mechanism of glomerular damage differs, depending on the source and dose of the antibody and the time after antibody administration (Boyce and Holdsworth, 1985;Salant and Cybulsky, 1988). When a low dosage of sheep NTS is given to mice, complement plays a significant role in the early heterologous phase of nephritis (Hebert et al, 1998;Quigg et al, 1998aQuigg et al, , 1998bSchrijver et al, 1988). This has been verified either by depleting serum complement proteins with cobra venom factor (Quigg et al, 1998b) or using C3 or C4 knock-out mice (Hebert et al, 1998). When the dosage of NTS is increased, the disease is in large part antibody mediated, and dependence on complement is diminished (Hebert et al, 1998). During the later autologous phase, especially if accelerated by preimmunization with heterologous IgG, a more fulminant, leukocyte-rich inflammatory lesion is induced (Lloyd et al, 1997).The sheep NTS used in these studies is specific for several podocyte cell surface proteins, including some that are known to be nephritogenic (Chugh et al, 2001). In addition, the proteinuria that develops in the early heterologous phase of g...