PLASMINOGEN AND PLASMINOGEN ACTIVATORS PROTECT AGAINST RENAL INJURY IN CRESCENTIC GLOMERULONEPHRITIS

The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and oth er matrix proteins. In human and experimental crescentic glomeruloneph ritis (GN), fibrin is an important mediator of glomerular injury and r enal impairment. Glomerular deposition of matrix proteins is a feature of progressive disease. To study the role of plasminogen and plasmino gen activators in the development of inflammatory glomerular injury, G N was induced in mice in which the genes for these proteins had been d isrupted by homologous recombination. Deficiency of plasminogen or com bined deficiency of tissue type plasminogen activator (tPA) and urokin ase type plasminogen activator (uPA) was associated with severe functi onal and histological exacerbation of glomerular injury. Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, al so exacerbated disease. uPA deficiency reduced glomerular macrophage i nfiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN. These studies demonst rate that plasminogen plays an important role in protecting the glomer ulus from acute inflammatory injury and that tPA is the major protecti ve plasminogen activator.