RESUMO
Complement factor D is a serine protease essential for the activation of the alternative pathway and is expressed in the kidney, adipocytes, and macrophages. Factor D is found at relatively high levels in glomeruli suggesting that this component of the complement cascade could influence renal pathophysiology. In this study, we utilize mice with a targeted deletion of the activating complement factor D gene and compare these results to mice with targeted deletion of the inhibitory complement factor H gene. Eight-month-old mice with a deleted factor D gene spontaneously develop albuminuria and have reduced creatinine clearance due to mesangial immune complex glomerulonephritis. These mesangial deposits contain C3 and IgM. In contrast to the mesangial location of the immune deposits in the factor D-deficient mice, age-matched factor H-deficient mice develop immune deposits along the glomerular capillary wall. Our observations suggest that complement factor D or alternative pathway activation is needed to prevent spontaneous accumulation of C3 and IgM deposits within the mesangium. Our studies show that the complement factor D gene knockout mice are a novel model of spontaneous mesangial immune complex glomerulonephritis.
Assuntos
Fator D do Complemento/deficiência , Glomerulonefrite/imunologia , Doenças do Complexo Imune/imunologia , Doenças do Complexo Imune/patologia , Albuminúria , Animais , Antígenos de Diferenciação/metabolismo , Capilares/imunologia , Capilares/metabolismo , Capilares/ultraestrutura , Complemento C3/imunologia , Complemento C3/metabolismo , Fator D do Complemento/genética , Fator H do Complemento/deficiência , Fator H do Complemento/genética , Creatinina/sangue , Creatinina/urina , Feminino , Fluoresceína-5-Isotiocianato , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes , Genótipo , Mesângio Glomerular/química , Mesângio Glomerular/imunologia , Mesângio Glomerular/patologia , Mesângio Glomerular/ultraestrutura , Glomerulonefrite/genética , Glomerulonefrite/patologia , Histocitoquímica , Doenças do Complexo Imune/genética , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Imuno-Histoquímica , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/ultraestrutura , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
INTRODUCTION: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology. SUBJECTS: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded. RESULTS: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls. CONCLUSION: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.