To prevent complement-mediated autologous tissue damage, host cells express a number of membrane-bound complement inhibitors. Decay-accelerating factor (DAF, CD55) is a GPI-linked membrane complement regulator that is widely expressed in mammalian tissues including the kidney. DAF inhibits the C3 convertase of both the classical and alternative pathways. Although DAF deficiency contributes to the human hematological syndrome paroxysmal nocturnal hemoglobinuria, the relevance of DAF in autoimmune tissue damage such as immune glomerulonephritis remains to be determined. In this study, we have investigated the susceptibility of knockout mice that are deficient in GPI-anchored DAF to nephrotoxic serum nephritis. Injection of a subnephritogenic dose of rabbit anti-mouse glomerular basement membrane serum induced glomerular disease in DAF knockout mice but not in wild-type controls. When examined at 8 days after anti-glomerular basement membrane treatment, DAF knockout mice had a much higher percentage of diseased glomeruli than wild-type mice (68.8 ± 25.0 vs 10.0 ± 3.5%; p < 0.01). Morphologically, DAF knockout mice displayed increased glomerular volume (516 ± 68 vs 325 ± 18 × 103 μm3 per glomerulus; p < 0.0001) and cellularity (47.1 ± 8.9 vs 32.0 ± 3.1 cells per glomerulus; p < 0.01). Although the blood urea nitrogen level showed no difference between the two groups, proteinuria was observed in the knockout mice but not in the wild-type mice (1.4 ± 0.7 vs 0.02 ± 0.01 mg/24 h albumin excretion). The morphological and functional abnormalities in the knockout mouse kidney were associated with evidence of increased complement activation in the glomeruli. These results support the conclusion that membrane C3 convertase inhibitors like DAF play a protective role in complement-mediated immune glomerular damage in vivo.
The complement system is indispensable for host defence. Unregulated activation, however, is related to various diseases. In order to elucidate the significance of complement, methodology that disrupts the complement system is essential. Advances in molecular genetics made direct modulations of the genes of complement components and their regulatory proteins feasible. One method is disruption of genes that encode complement components. Several studies have been conducted with these mice in models such as nephrotoxic serum (NTS) nephritis, ischaemia reperfusion and immune complex-mediated glomerulonephritis. These studies all showed that depletion of complement components ameliorated the severity of the diseases. Complement regulatory protein serves a regulatory role in the complement system. Genetically engineered animals that overexpress these proteins have been employed to elucidate their biological roles. Mice overexpressing soluble complement regulatory proteins were protected from the lesion of both NTS and the glomerular endothelial injury model. In contrast, knockout mice that lack expression of decay-accelerating factor (DAF), a complement regulatory protein, developed severe glomerular lesions when subnephritogenic doses of NTS were administered. These genetically engineered animals shed light on the mechanism of initiation and progression of kidney disease.
The mAb 1-22-3-induced GN in a uninephrectomized rat model simulates the clinical manifestations of human disease, indicating that this model may be useful for studying progressive renal failure and for investigating new therapeutic strategies against renal failure.
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