Tissue factor, plasminogen activator inhibitor-1, and thrombin receptor expression in human crescentic glomerulonephritis

Glomerular fibrin deposition is a common histological feature of crescentic glomerulonephritis (CGN). Tissue factor (TF) is the most powerful activato r of the coagulation system, whereas plasminogen activator inhibitor (PAI)- 1 is a key modulator of the fibrinolytic pathway. Thrombin, released locall y as the final step of the coagulation cascade and trapped within the fibri n clots, can induce the activation of glomerular cells, through the interac tion with a specific receptor. To investigate the mechanisms underlying coa gulation cascade activation and fibrin deposition and the role of this phen omenon in the pathogenesis of human CGN, TF, PAI-1, and thrombin receptor e xpression were studied in CGN biopsy specimens. Glomerular TF gene and prot ein expression were strikingly increased in CGN, in particular within the c rescents and in the mesangial area, with the same distribution of fibrin de posits. Interestingly, very few infiltrating mononuclear cells were stained in TF Immunohistochemistry. To better evaluate the involvement of monocyte s in TF expression, TF mRNA and CD68 protein were studied by an in situ hyb ridization/immunohistochemistry combined technique. Only 16% of the cells e xpressing TF mRNA were CD68 positive. However, most of the TF signal was lo calized in the proximity of monocytes, suggesting that soluble mediator(s) released by these cells could induce TF expression. Indeed, Interleukin-l ( IL-l), one of the main monocyte-derived cytokines, upregulated TF mRNA leve ls In cultured human mesangial cells In a time-dependent manner. Moreover, a striking increase in IL-1 expression was present within the cellular cres cents in CGN biopsy specimens. Finally, we observed a marked upregulation o f both PAI-1 and thrombin receptor mRNA levels In CGN with a pattern resemb ling TF and fibrin distribution. Surprisingly, thrombin receptor protein ex pression was strikingly downregulated in CGN, suggesting its continuous act ivation and degradation. In conclusion, we can hypothesize that TF and PAI- 1, mainly expressed by resident cells, may play a pivotal role In the devel opment and preservation of fibrin deposits in CGN. In addition, thrombin, r eleased locally and accumulated within the fibrin clots, may represent a pa thogenetic mediator of crescentic lesions. (C) 2000 by the National Kidney Foundation, Inc.