title: Tissue factor, plasminogen activator inhibitor-1, and thrombin receptor expression in human crescentic glomerulonephritis.
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.
authors.affiliation: Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Grandaliano
authors.forename: L
authors.initials: L
authors.lastname: Gesualdo
authors.forename: E
authors.initials: E
authors.lastname: Ranieri
authors.forename: R
authors.initials: R
authors.lastname: Monno
authors.forename: F P
authors.initials: FP
authors.lastname: Schena
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015152:Blotting, Northern; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium / Q000737:chemistry; D005921:Glomerulonephritis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000032:analysis; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D018179:Receptors, Thrombin / Q000032:analysis*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000032:analysis* / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D018179:Receptors, Thrombin; D013917:Thrombin; D013925:Thromboplastin; C067980:CD68 antigen, human; D000097382:CD68 Molecule