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.