Renal expression of tissue factor pathway inhibitor and evidence for a role in crescentic glomerulonephritis in rabbits.

Erlich, Jonathan; Apostolopoulos, Jim; Wun, TC; Kretzmer, Kuniko K.; Holdsworth, Stephen R.; Tipping, Peter G.

doi:10.1172/jci118796

Cited by 39 publications

(31 citation statements)

References 36 publications

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“…Fibrin deposition in crescentic GN is initiated by local upregulation of tissue factor (34,35) and is dependent on glomerular macrophage infiltration (36). Tissue factor is expressed by glomerular macrophages (37), and its expression on glomerular epithelial cells (38), mesangial cells (22), and endothelial cells (39) is induced by TNF.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis

Timoshanko¹,

Sedgwick²,

Holdsworth³

et al. 2003

Journal of the American Society of Nephrology

108

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Abstract. Macrophages are prominent participants in crescentic glomerulonephritis (GN) and have been suggested to be the major source of TNF in this cell-mediated form of glomerular inflammation. Intrinsic renal cells also have the capacity to produce TNF. For dissecting the contribution of local versus bone marrow (BM)-derived TNF in inflammatory renal injury, TNF chimeric mice were created by transplanting normal wildtype (WT) BM into irradiated TNF-deficient recipients (WT3 TNF Ϫ/Ϫ chimeras) and vice versa (TNF Ϫ/Ϫ 3 WT chimeras). A model of crescentic GN induced by an intravenous injection of sheep anti-murine glomerular basement membrane antibody was studied in WT mice, mice with complete TNF deficiency (TNFϪ/Ϫ), and chimeric mice. Crescentic GN was attenuated in TNFϪ/Ϫ mice with fewer crescents (crescents, 13.7 Ϯ 1.7% of glomeruli) and reduced functional indices of renal injury (serum creatinine, 15.2 Ϯ 0.8 mol/L). Similar protection (crescents, 14.3 Ϯ 1.9% of glomeruli; serum creatinine, 18.9 Ϯ 1.1 mol/L) was observed in chimeric mice with intact BM but absent renal-derived TNF (WT3 TNF Ϫ/Ϫ chimeras), suggesting a minor contribution of infiltrating leukocytes to TNF-mediated renal injury. Chimeric mice with TNFdeficient leukocytes but intact intrinsic renal cell-derived TNF (crescents, 20.5 Ϯ 2.0% of glomeruli; serum creatinine, 21.6 Ϯ 1.4 mol/L) developed similar crescentic GN to WT mice (crescents, 22.3 Ϯ 1.4% of glomeruli; serum creatinine, 24.8 Ϯ 1.9 mol/L). Cutaneous delayed-type hypersensitivity after subdermal challenge with the nephritogenic antigen was attenuated in the absence of BM cell-derived TNF but unaffected in WT3 TNF Ϫ/Ϫ chimeric mice. These studies suggest that intrinsic renal cells are the major cellular source of TNF contributing to inflammatory injury in crescentic GN.

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Section: Discussionmentioning

confidence: 99%

Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis

Timoshanko¹,

Sedgwick²,

Holdsworth³

et al. 2003

Journal of the American Society of Nephrology

108

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“…46,47 Blocking TFPI in a rabbit model of fibrindependent glomerulonephritis augments the deposition of glomerular fibrin and renal injury. 48 Whether native TFPI also associates with fibrin in vivo and, if it does, whether it preserves the functional activity after fibrinolysis are issues that require elucidation. In advanced complicated plaques (popliteal arteries with thrombus, type VI lesions), we observed strong colocalization between TFPI and the platelet marker ␣ IIb ␤ 3 or the fibrin monomer II, which prevails over fibrin monomer I in the thrombotic regions of the plaques.…”

Section: Discussionmentioning

confidence: 99%

Expression, Localization, and Activity of Tissue Factor Pathway Inhibitor in Normal and Atherosclerotic Human Vessels

Crawley

Lupu

Westmuckett

et al. 2000

ATVB

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Abstract-Tissue factor (TF) pathway inhibitor (TFPI) is the major downregulator of the procoagulant activity of the TF-factor VIIa (FVIIa) complex (TF ⅐ FVII). The active TF present in the atherosclerotic vessel wall is proposed to be responsible for the major complication of primary atherosclerosis, namely, acute thrombosis after plaque rupture, but our knowledge of the sites of TFPI expression in relation to TF remains fragmentary. The aim of this study was to investigate the expression, localization, and activity of TFPI and its relation to the activity and distribution of TF in the normal and atherosclerotic vessel wall. We applied a novel approach in which serial cross sections of human vascular segments were used to perform a complete set of assays: immunolabeling for TFPI and/or TF, in situ hybridization for the expression of TFPI mRNA, ELISA for the determination of TFPI antigen, and functional assay for the activity of TFPI and TF. In healthy vessels, TFPI protein and mRNA are present in luminal and microvascular endothelial cells (ECs) and in the medial smooth muscle cells (SMCs). In atherosclerotic vessels, TFPI protein and mRNA frequently colocalized with TF in ECs overlying the plaque and in microvessels, as well as in the medial and neointimal SMCs, and in macrophages and T cells in areas surrounding the necrotic core. At the ultrastructural level, immunogold electron microscopy confirmed the localization of TFPI in ECs, macrophages/foam cells, and SMCs. In ECs and SMCs, the gold particles decorated the plasmalemma proper and the caveolae. ELISA on cross sections revealed that atherosclerotic tissues contain more TFPI than do the healthy vessels. TFPI was functionally active against TF ⅐ FVIIa-induced coagulation, and its activity was higher in those tissues that display less TF. The largest amount of TFPI and TF were detected in complicated arterial plaques. By immunofluorescence, TFPI colocalized with platelet-and fibrin-rich areas within the organized thrombi. Atherosclerotic vessel sections promote activation of factor X, which is dependent on the presence of TF and enhanced by preincubation of the sections with anti-TFPI IgG. Taken altogether, our results suggest that TFPI is largely expressed in the normal vessel wall and enhanced in the atherosclerotic vessel, in a manner suggesting a significant role of TFPI in the regulation of TF activity.

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“…In human glomerulonephritis, TFPI is detected in glomeruli showing extracapillary proliferation (38,39). Immunoperoxidase staining suggests that endothelial cells are the main physiologic source of TFPI and/or the main binding site.…”

Section: Key Players In Fibrin Formation and Destructionmentioning

confidence: 99%

“…Immunoperoxidase staining suggests that endothelial cells are the main physiologic source of TFPI and/or the main binding site. During crescentic glomerulonephritis in rabbits, TFPI synthesis is initially downregulated, potentially enhancing TF activity and thereby facilitating fibrin deposition (38). Early infusion of recombinant human TFPI attenuates both glomerular fibrin deposition and renal impairment, suggesting that this recombinant protein could have therapeutic potential in fibrinous glomerulopathies.…”

Section: Key Players In Fibrin Formation and Destructionmentioning

confidence: 99%

Role of the Coagulation/Fibrinolysis System in Fibrin-Associated Glomerular Injury

Hertig¹,

Rondeau²

2004

Journal of the American Society of Nephrology

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Abstract. In the past decade, numerous experimental studies of genetically engineered mice have confirmed the involvement of the coagulation/fibrinolysis system during glomerular inflammation and repair, revealing many unexpected biologic effects far beyond fibrin formation and clearance. Resident glomerular cells and macrophages seem to act in concert to ensure the long-term consolidation of local injury and progression toward glomerulosclerosis. These recent advances will probably pave the way to a new therapeutic approach to renal diseases. However, the balance governing glomerular permeability is very delicate, and many issues will have to be dealt with before targeting this system. Fibrin deposition is a prominent feature of crescentic glomerulonephritis and of the hemolytic uremic syndrome (HUS). Fibrin clots not only interrupt capillary blood flow, leading to irreversible ischemia and glomerular obsolescence, but also promote the influx of monocyte-macrophages and proliferation of epithelial cells in Bowman's space (Figure 1). It therefore is important to understand the mechanisms underlying fibrin formation (i.e., activation of intraglomerular coagulation) and fibrin persistence (i.e., deficiency of the fibrinolysis system). Major advances have been made during the past decade, notably by using mice in which key factors in the coagulation/ fibrinolysis pathways were genetically altered. Two principal notions have emerged. First, the glomerulus must no longer be seen as a regular capillary ball whose main function is blood ultrafiltration but as an autarchic multicellular structure finely regulating its own vascular permeability. Second, most of the mediators involved have specific, nonredundant properties that extend beyond the vascular compartment and fibrin formation per se, also controlling inflammation and lesion repair. We review the most recent findings in this field and identify the major outstanding questions.

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Renal expression of tissue factor pathway inhibitor and evidence for a role in crescentic glomerulonephritis in rabbits.

Cited by 39 publications

References 36 publications

Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis

Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis

Expression, Localization, and Activity of Tissue Factor Pathway Inhibitor in Normal and Atherosclerotic Human Vessels

Role of the Coagulation/Fibrinolysis System in Fibrin-Associated Glomerular Injury

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