mRNA expression of urokinase and plasminogen activator inhibitor-1 in human crescentic glomerulonephritis

Aims: Weak staining for urokinase-plasminogen activator (uPA), tissue type plasminogen activator (tPA), or plasminogen activator inhibitor-1 (PAI-1) confined to crescents has been described in a few cases of severe crescentic glomerulonephritis. We evaluated the molecular mechanism by which these proteins are increased or induced within crescents. Methods and results: We examined uPA, tPA and PAI-1 mRNA expression in 12 renal biopsies with crescentic glomerulonephritis, and in six control renal biopsies with no detectable abnormalities by RNA in-situ hybridization. The expressions of uPA, tPA and PAI-1 proteins were also assessed by immunofluorescence. To better determine the cellular origin of uPA and PAI-1 transcripts, CD68 protein was studied by immunohistochemistry on the same sections on which in-situ hybridization had been performed. In controls, there were very low level signals of uPA and PAI-1 mRNAs in a few glomerular epithelial cells (GECs). Specific signals of uPA and PAI-1 mRNAs were detected in the cells forming crescents in all the cases with crescentic glomerulonephritis. However, weak expression of mRNA for tPA was detected in two cases only. Immunostaining for uPA and PAI-1 was positive in some but not all, cases of crescentic glomerulonephritis. A double-labelling study showed that the signal for PAI-1 and uPA mRNAs was mainly in CD68- cells. Conclusions: Local accumulation of uPA or PAI-1 in crescents is associated with enhanced mRNA expression of these proteins. The up-regulation of PAI-1 mRNA by GECs, in particular, could play a major role in the formation of persistent fibrin deposits and progression of the lesions in crescents. Whether up-regulation of uPA is an epiphenomenon or plays a pathogenic role in the formation of crescents remains to be clarified.