EXPRESSION OF TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR IN RENAL TISSUE IN MURINE LUPUS NEPHRITIS

Many renal diseases are associated with fibrin deposition in the glome ruli, a situation that reflects an abnormality in the balance between the coagulation and fibrinolytic systems. We recently demonstrated tha t normal mouse kidney contains very low levels of type 1 plasminogen a ctivator inhibitor (PAI-1), a potent anti-fibrinolytic protein, but th at during endotoxemia, large amounts of PAI-1 protein and mRNA are exp ressed in glomerular and peritubular endothelial cells. These results raise the possibility that overexpression of PAI-1 in the glomerulus m ay contribute to the ongoing pathology seen in renal disease. To direc tly investigate this possibility we studied PAI-1 expression in MRL/lp r mice, using in situ hybridization and immunohistochemistry. Female M RL/lpr mice develop early onset lupus glomerulonephritis (GN), a disea se in which fibrin deposition is detected in the glomerulus and in whi ch anti-coagulation therapy improves the prognosis. We detected very l ow levels of PAI-1 mRNA and antigen in the smooth muscle cells of rena l vessels and in the renal papilla of 16 control mice. In contrast, PA I-1 was expressed in relatively high levels throughout the kidneys of 33 out of 34 diseased mice, both within the glomerulus and also in tub ules and vessels. Moreover, the level of PAI-1 in the tissues seemed t o correlate with the severity of the disease. PAI-1 expression was loc alized to endothelial cells, parietal epithelial cells, tubular epithe lial cells and infiltrating mononuclear cells in the tubulointerstitiu m. None of these cells express detectable levels of PAI-1 in the norma l kidney. The inappropriate expression of PAI-1 in the kidneys of mice with lupus GN suggests that this important inhibitor of fibrinolysis may play a role in the pathogenesis of this disease process.