title: Renal microvascular injury induced by antibody to glomerular endothelial cells is mediated by C5b-9.
abstract: We have recently developed a model of thrombotic microangiopathy with injury to the glomerular endothelial cell (GEN) induced by heterologous antibody to rat GEN. In addition to GEN injury rats developed glomerular platelet aggregation and fibrin deposition, acute renal failure, and acute tubular necrosis with interstitial inflammation. To study the role of complement in mediating this lesion, we induced the disease in normal complement PVG rats and measured the effects of generalized complement depletion with cobra venom factor (CVF) and of selective C6 deficiency using genetically C6 deficient PVG animals. Complement sufficient rats developed severe endothelial injury accompanied by platelet aggregation, fibrin deposition, decrease in endothelial cells assessed by antibody staining in the glomerulus, and macrophage infiltration. These changes were associated with marked reduction in renal function. These features were either absent or markedly diminished in complement depleted or C6 deficient rats. This demonstrates that C5b-9, the terminal product of activation of the complement cascade, plays an important role in the pathogenesis of this immune renal microvascular endothelial injury model. Thus, the complement system may play a pathogenic role in renal microvascular diseases such as thrombotic microangiopathy.
authors.affiliation: Division of Nephrology, University of Washington, Seattle, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nangaku
authors.forename: C E
authors.initials: CE
authors.lastname: Alpers
authors.forename: J
authors.initials: J
authors.lastname: Pippin
authors.forename: S J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: K
authors.initials: K
authors.lastname: Kurokawa
authors.forename: S
authors.initials: S
authors.lastname: Adler
authors.forename: R J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: W G
authors.initials: WG
authors.lastname: Couser
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000503:physiopathology; D000818:Animals; D001792:Blood Platelets; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D003183:Complement C6 / Q000172:deficiency; D015941:Complement Hemolytic Activity Assay; D015938:Complement Membrane Attack Complex / Q000032:analysis / Q000276:immunology*; D004195:Disease Models, Animal; D004727:Endothelium / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D005337:Fibrin / Q000032:analysis; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000032:analysis; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000276:immunology* / Q000648:ultrastructure; D008264:Macrophages / Q000276:immunology; D008297:Male; D008833:Microcirculation / Q000276:immunology; D008854:Microscopy, Electron; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D003176:Complement C3; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D005337:Fibrin