Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies.
Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with beta(2) glycoprotein I (beta2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.
Seshan
Surya V
SV
Department of Pathology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Franzke
Claus-Werner
CW
Redecha
Patricia
P
Monestier
Marc
M
Mackman
Nigel
N
Girardi
Guillermina
G
D000328:Adult; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000937:Antigen-Antibody Reactions / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D051437:Renal Insufficiency / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D013925:Thromboplastin