STIMULATION OF PAI-1 IN RABBIT ANTI-GBM GLOMERULONEPHRITIS

It has previously been shown in human disease and animal models of glo merulonephritis (GN) that fibrin deposition is associated with a net r eduction of glomerular fibrinolytic activity as a result of reduced ex pression of plasminogen activators and increased expression of plasmin ogen activator inhibitor type 1 (PAI-1). Conditioned media (CM) prepar ed from cultured glomeruli of normal rabbits and rabbits 24 (Day 1) an d 96 (Day 4) h after induction of anti-GEM GN were compared for their effects on the synthesis of fibrinolytic molecules in human endothelia l cells (EC). Only CM from Day 4 GN rabbits showed PAI 1 protein stimu latory activity of up to 148% (P<0.05; n=3) above that of untreated EC . This was also seen at the mRNA level. Glomerulonephritis Day 4 CM sh owed significantly higher amounts of tumour necrosis factor (TNF) and thrombin and transforming growth factor-beta (TGF-beta) bioactivity in comparison to glomerular CM from normal rabbits. After high performan ce liquid chromatography (HPLC) of Day 4 GN CM, PAI-1 stimulatory acti vity was found to correlate with the presence of interleukin 1 (IL-1), TNF and TGF-beta. These results suggest a correlation between severit y of anti-GEM GN in a rabbit model, increased PAI-1 synthesis and incr eased expression of TNF and TGF-beta. This may potentiate glomerular f ibrin and extracellular matrix deposition in anti-GEM GN, leading to g lomerular crescent formation and eventual renal failure.