The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis.
Quantitative reverse transcription polymerase chain reaction and in situ hybridization were employed to investigate the expression of tissue-type and urokinase-type plasminogen activators (t-PA and u-PA, respectively), of their specific inhibitor (PAI-1), and of the procoagulant molecule tissue factor (TF) in tissues from mice that develop autoimmune disease (MRL lpr/lpr). A dramatic increase in PAI-1 activity in plasma and in PAI-1 mRNA in the kidneys was observed in these mice, and this increase appeared to correlate with the progression of lupus nephritis. The increase in PAI-1 mRNA was relatively specific for the kidney as little or no change was observed in most other tissues. One exception was the brain where PAI-1 mRNA was also significantly higher in the diseased mice. In addition to these changes in PAI-1, decreases in u-PA mRNA and increases in TF mRNA were demonstrated in kidneys from the lupus-prone mice. These changes also correlated with the development of lupus nephritis and with spontaneous glomerular and peritubular fibrin deposition in the nephritic kidney. In this regard, the MRL lpr/lpr mice were found to be considerably more sensitive to endotoxin than the normal controls, developing fibrin deposits in the kidneys and other tissues at 10- to 20-fold lower concentrations of this toxic agent. The increase in PAI-1 and TF mRNAs and the decrease in u-PA mRNA in the kidneys of MRL lpr/lpr mice suggests that changes in the expression of these genes may promote the formation of microthrombi and thus contribute to the progression of lupus nephritis in this model.
Yamamoto
K
K
Department of Vascular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Loskutoff
D J
DJ
D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D017403:In Situ Hybridization; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008177:Lupus Vulgaris / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D005337:Fibrin; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator