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Tissue factor, plasminogen activator inhibitor-1, and thrombin receptor expression in human crescentic
G Grandaliano1, L Gesualdo, E Ranieri
1Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Italy.
Insights
Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 are key in crescentic glomerulonephritis (CGN) fibrin deposition. Thrombin, trapped in clots, likely drives crescent formation in CGN.
Area of Science:
- Nephrology
- Pathology
- Hematology
Background:
- Glomerular fibrin deposition is a hallmark of crescentic glomerulonephritis (CGN).
- Tissue factor (TF) activates coagulation, while plasminogen activator inhibitor (PAI)-1 modulates fibrinolysis.
- Thrombin, a coagulation product, may activate glomerular cells via its receptor.
Purpose of the Study:
- To investigate mechanisms of coagulation activation and fibrin deposition in human CGN.
- To elucidate the role of TF, PAI-1, and thrombin receptor in CGN pathogenesis.
Main Methods:
- Analysis of TF, PAI-1, and thrombin receptor expression in CGN biopsy specimens.
- In situ hybridization and immunohistochemistry to assess cell-specific expression (TF mRNA, CD68).
- In vitro study of interleukin-1 (IL-1) effects on mesangial cells.
Main Results:
- Significantly increased glomerular TF gene and protein expression in CGN, co-localizing with fibrin.
- TF expression primarily by resident cells, not infiltrating monocytes, though proximity suggests monocyte-derived mediators (e.g., IL-1) induce TF.
- Upregulated PAI-1 and thrombin receptor mRNA, but downregulated thrombin receptor protein, suggesting activation and degradation.
Conclusions:
- TF and PAI-1, produced by resident cells, are crucial for fibrin deposit development and maintenance in CGN.
- Locally released thrombin within fibrin clots may act as a pathogenetic mediator of crescentic lesions.
- IL-1 signaling contributes to TF upregulation in CGN.
Abstract:
Glomerular fibrin deposition is a common histological feature of crescentic glomerulonephritis (CGN). Tissue factor (TF) is the most powerful activator of the coagulation system, whereas plasminogen activator inhibitor (PAI)-1 is a key modulator of the fibrinolytic pathway. Thrombin, released locally as the final step of the coagulation cascade and trapped within the fibrin clots, can induce the activation of glomerular cells, through the interaction with a specific receptor. To investigate the mechanisms underlying coagulation cascade activation and fibrin deposition and the role of this phenomenon in the pathogenesis of human CGN, TF, PAI-1, and thrombin receptor expression were studied in CGN biopsy specimens. Glomerular TF gene and protein expression were strikingly increased in CGN, in particular within the crescents and in the mesangial area, with the same distribution of fibrin deposits. Interestingly, very few infiltrating mononuclear cells were stained in TF immunohistochemistry. To better evaluate the involvement of monocytes in TF expression, TF mRNA and CD68 protein were studied by an in situ hybridization/immunohistochemistry combined technique. Only 16% of the cells expressing TF mRNA were CD68 positive. However, most of the TF signal was localized in the proximity of monocytes, suggesting that soluble mediator(s) released by these cells could induce TF expression. Indeed, interleukin-1 (IL-1), one of the main monocyte-derived cytokines, upregulated TF mRNA levels in cultured human mesangial cells in a time-dependent manner. Moreover, a striking increase in IL-1 expression was present within the cellular crescents in CGN biopsy specimens. Finally, we observed a marked upregulation of both PAI-1 and thrombin receptor mRNA levels in CGN with a pattern resembling TF and fibrin distribution. Surprisingly, thrombin receptor protein expression was strikingly downregulated in CGN, suggesting its continuous activation and degradation. In conclusion, we can hypothesize that TF and PAI-1, mainly expressed by resident cells, may play a pivotal role in the development and preservation of fibrin deposits in CGN. In addition, thrombin, released locally and accumulated within the fibrin clots, may represent a pathogenetic mediator of crescentic lesions.