DYSFUNCTION OF GLOMERULAR FIBRINOLYSIS IN EXPERIMENTAL ANTIGLOMERULARBASEMENT-MEMBRANE ANTIBODY GLOMERULONEPHRITIS

Glomerular plasminogen activator inhibitor-1 (PAI-1) steady-state mRNA and bioactivity were increased after the induction of an augmented fo rm of antiglomerular basement membrane (GBM) antibody glomerulonephrit is. PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and alth ough falling thereafter, remained higher than that of the control grou p through Day 17. PAI-1 mRNA expression correlated with glomerular PAI -1 bioactivity as determined by a functional tissue type plasminogen a ctivator (t-PA) binding assay. Glomerular PAI-1 bioactivity, not detec ted in controls, increased to 1.4 +/- 0.3 ng/mg of glomerular lysate a t 6 h and then decreased to 0.7 +/- 0.1 ng/mg of glomerular lysate by Day 6. The mRNA of the plasminogen activators (urokinase plasminogen a ctivator, t-PA) either remained unchanged or declined through Day 1, w ith a slight increase in t-PA mRNA at Day 6. Interleukin-1beta mRNA ex pression was maximal at 6 h, declining by Day 3. Transforming growth f actor beta1 (TGF-beta1) mRNA began to increase at Day 1, was maximal a t Day 6, and fell only slightly by Day 17. Epidermal growth factor mRN A decreased. The increase in PAI-1 mRNA and bioactivity, possibly indu ced early by the interleukin-1beta response and perhaps later by the T GF-beta1 response, was associated with striking glomerular capillary l umen fibrin accumulations on Day 1, which decreased and appeared to re canalize as the PAI-1 mRNA and bioactivity fell. The glomerular lesion continued to have some fibrin deposits even on Day 17 and, in additio n, had changes of thickened GBM, suggestive of the early stages of dif fuse glomerulosclerosis. The latter had a temporal relationship with t he persisting increase in TGF-beta1 and PAI-1 mRNA levels. These obser vations suggest the possibility that inhibition of enzymes capable of remodeling excessive extracellular matrix production may have contribu ted to the thickened GBM.