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 si tu hybridization were employed to investigate the expression of tissue -type and urokinase-type plasminogen activators (t-PA and u-PA, respec tively), of their specific inhibitor (PAI-1), and of the procoagulant molecule tissue factor (TF) in tissues from mice that develop autoimmu ne disease (MRL lpr/lpr), A dramatic increase in PAI-1 activity in pla sma and in PAI-1 mRNA in the kidneys was observed in these mice, and t his increase appeared to correlate with the progression of lupus nephr itis, The increase in PAI-1 mRNA was relatively specific for the kidne y as little or no change was observed in most other tissues. One excep tion was the brain where PAI-1 mRNA was also significantly higher in t he 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 t he lupus-prone mice, These changes also correlated with the developmen t of lupus nephritis and with spontaneous glomerular and peritubular f ibrin deposition in the nephritic kidney, In this regard, the MRL lpr/ lpr mice were found to be considerably more sensitive to endotoxin tha n the normal controls, developing fibrin deposits in the kidneys and o ther tissues at 10- to 20-fold lower concentrations of this toxic agen t, 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 expressi on of these genes may promote the formation of microthrombi and thus c ontribute to the progression of lupus nephritis in this model.