Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation

Tanaka, Misa; Arai, Hidenori; Liu, Ning; Nogaki, Fumiaki; Nomura, Keiko; Kasuno, Kenji; Oida, Emi; Kita, Toru; Ono, Takahiko

doi:10.1111/j.1523-1755.2005.00317.x

Cited by 37 publications

(32 citation statements)

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“…46 In our recent study, we reported that PAR2 is expressed in cultured human mesangial cells, and that factor Xa induces cellular proliferation through the activation of ERK via PAR2. 7 In this study, high-dose DX-9065a suppressed both PCNA-positive cells and total glomerular cells, whereas a low dose of this inhibitor suppressed only total glomerular cells on day 8. Regarding this discrepancy, it was suspected that sufficient concentration of DX-9065a in renal tissue to suppress PCNA-positive cells in the later phase of nephritis might be maintained only by a high dose, and that the concentration from a low-dose injection might suppress only cellular proliferation in the early phase, and subsequently total glomerular cells in the later phase, but might Figure 6 Inhibitory effects of DX-9065a on PCNA-positive cell number.…”

Section: Roles Of Factor Xa In Rat Mspgnmentioning

confidence: 47%

“…5,6 We have also shown that factor Xa induces cellular proliferation through the activation of extracellular regulated kinase (ERK)1/2 via protease-activated receptor 2 (PAR2) in cultured human mesangial cells, and that DX9065a, a small synthetic molecule, and a specific Xa inhibitor, suppresses their proliferation. 7 DX-9065a can competitively inhibit human factor Xa (Ki value: 0.041 mM). 8 Recently reported effects of this drug include activity to regulate coagulation and proliferation 9 in vivo and in vitro.…”

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confidence: 99%

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Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura

Liu

Nagai

et al. 2007

Laboratory Investigation

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Tissue factor initiates the extrinsic coagulation pathway by activating coagulation factor X to factor Xa, and factor V is a cofactor for the prothrombin activation by factor Xa. As factor Xa is known to promote the proliferation of mesangial cells in culture, the roles of the coagulation pathway and factor Xa were studied in an animal model of mesangioproliferative glomerulonephritis (MsPGN). MsPGN was induced in Wistar rats by an intravenous injection of anti-Thy 1.1 monoclonal antibody, OX-7. To clarify the role of factor Xa in MsPGN, a specific factor Xa inhibitor, DX-9065a, was injected intravenously at 2.5 or 10 mg/kg at the same time as OX-7, and kidney involvement was assessed by immunohistological analyses. We also examined p44/42 mitogen-activated protein (MAP) kinase activation. Time-course study revealed that expressions of tissue factor, factor V, and protease-activated receptor 2 (PAR2) were peaked on day 3, followed by factor X accumulation and mesangial proliferation. DX-9065a treatment significantly ameliorated proteinuria in a dose-dependent manner on day 8. Histological analyses showed a significant reduction in the size of glomeruli, the total number of glomerular cells, and crescent formation by DX-9065a treatment. Macrophage infiltration, which was rapidly observed on day 1 in disease control rats was not inhibited on days 1-3 by DX-9065a treatment, however it was suppressed on days 5-8. The deposition of fibrin, the number of PCNA-positive cells, and phosphorylation of p44/42 MAP kinase were markedly increased in the disease control group, whereas they were significantly reduced in the treatment group. Tissue factor and factor V induction may accelerate MsPGN through the activation and accumulation of factor X via proinflammatory and procoagulant mechanisms, and the inhibition of factor Xa would be a promising method to regulate the disease process.

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Section: Roles Of Factor Xa In Rat Mspgnmentioning

confidence: 47%

mentioning

confidence: 99%

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura

Liu

Nagai

et al. 2007

Laboratory Investigation

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“…It has previously been shown in a number of other cell types that PAR-2 activation can stimulate the ERK1/2 MAPK pathway (21,32). This in turn can mediate a range of responses including, notably, cell proliferation.…”

Section: Discussionmentioning

confidence: 96%

Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation

Vesey¹,

Kruger²,

Poronnik³

et al. 2007

American Journal of Physiology-Renal Physiology

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Despite the abundant expression of protease-activated receptor (PAR)-2 in the kidney, its relevance to renal physiology is not well understood. A role for this receptor in inflammation and cell proliferation has recently been suggested in nonrenal tissues. The aims of this study were to demonstrate that human proximal tubule cells (PTC) express functional PAR-2 and to investigate whether its activation can mediate proinflammatory and proliferative responses in these cells. Primary human PTC were cultured under serum-free conditions with or without the PAR-2-activating peptide SLIGKV-NH2 (up to 800 μM), a control peptide, VKGILS-NH2 (200 μM), or trypsin (0.01–100 nM). PAR-2 expression (RT-PCR), intracellular Ca2+ mobilization (fura-2 fluorimetry), DNA synthesis (thymidine incorporation), fibronectin production (ELISA, Western blotting), and monocyte chemotactic protein (MCP)-1 secretion (ELISA) were measured. Trypsinogen expression in kidney and PTC cultures was determined by immunohistochemistry and Western blotting. In the kidney PTC were the predominant cell type expressing PAR-2. SLIGKV-NH2, but not VKGILS-NH2, stimulated a rapid concentration-dependent mobilization of intracellular Ca2+ and ERK1/2 phosphorylation and, by 24 h, increases in DNA synthesis, fibronectin secretion, and MCP-1 secretion. These delayed responses appeared to be independent of ERK1/2. Trypsin produced similar rapid but not delayed responses. Trypsinogen was weakly expressed by PTC in the kidney and in culture. In summary, PTC are the main site of PAR-2 expression in the human kidney. In PTC cultures SLIGKV-NH2 initiates proinflammatory and proliferative responses. Trypsinogen expressed within the kidney has the potential to contribute to PAR-2 activation in certain circumstances.

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“…37) PAR2 is expressed in cultured human mesangial cells, and factor Xa induces cellular proliferation through the activation of extracellular regulated kinase (ERK) via PAR2, as demonstrated previously by our group. 38) Yamamoto et al reported that tumstatin peptide, an inhibitor of angiogenesis, prevented glomerular hypertrophy in the early stage of streptozotocininduced diabetic nephropathy. 21) Recently, Uusitalo-Jarvinen et al have shown using genetically deficient mice that PAR1 and PAR2 play roles in hypoxia-driven angiogenesis and that PAR2 signaling is sufficient for this proangiogenic effect.…”

Section: Discussionmentioning

confidence: 99%

Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice

Sumi

Yamanaka-Hanada

Bai

et al. 2011

Biological & Pharmaceutical Bulletin

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The active type of coagulation factor X (factor Xa) activates various cell-types through protease-activated receptor 2 (PAR2). We previously reported that a factor Xa inhibitor could suppress Thy-1 nephritis. Considering that fibrin deposition is observed in diabetic nephropathy as well as in glomerulonephritis, this study examined the roles of the coagulation pathway and factor Xa in the development of diabetic nephropathy using type 2 diabetic model mice. Diabetic (db/db) and normoglycemic (m؉/m؉) mice were immunohistochemically evaluated for their expression/deposition of PAR2, transforming growth factor (TGF)-b b, fibrin, extracellular matrix (ECM) proteins, and CD31 at week 20. Significantly greater numbers of PAR2-positive cells and larger amounts of fibronectin, and collagen IV depositions were observed in the glomeruli of db/db mice than those in m؉/m؉ mice. Next, expression of PAR2 versus deposition of collagen IV and fibronectin was compared between week 20 and week 30, and the number of PAR2-positive cells in the glomeruli decreased in contrast with the increased accumulation of ECM proteins. In an intervention study, fondaparinux, a factor Xa inhibitor, was subcutaneously administered for ten weeks from week 10 to 20. Fondaparinux treatment significantly suppressed urinary protein, glomerular hypertrophy, fibrin deposition, expression of connective tissue growth factor, and ECM proteins deposition together with CD31-positive capillaries. These results suggest that coagulation pathway and glomerular PAR2 expression are upregulated in the early phase of diabetes, together with the increase of profibrotic cytokines expression, ECM proteins deposition and CD-31-positive vessels. Factor Xa inhibition may ameliorate glomerular neoangiogenesis and ECM accumulation in diabetic nephropathy.

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Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation

Cited by 37 publications

References 50 publications

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation

Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice

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