Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura, Keiko; Liu, Ning; Nagai, Kojiro; Hasegawa, Takamichi; Kobayashi, I; Nogaki, Fumiaki; Tanaka, Misa; Arai, Hidenori; Fukatsu, Atsushi; Kita, Toru; Ono, Takahiko

doi:10.1038/labinvest.3700502

Cited by 29 publications

(27 citation statements)

References 44 publications

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“…Importantly, specific FXa inhibition is beneficial in rat model of mesangioproliferative glomerulonephritis, in part by reducing fibrin deposition. 37 We recently showed FXa stimulated fibroblast proliferation, differentiation into myofibroblast and the expression of profibrotic proteins via PAR-2 activation. 13 Next to a direct role on fibroblast activation during pulmonary fibrosis, PAR-2 activation may well aggravate fibrosis by modulating epithelial barrier functions.…”

Section: Discussionmentioning

confidence: 99%

“…56 Further support for an important role of FXa-PAR-2 in fibrosis is derived from a rat model of mesangioproliferative glomerulonephritis showing that both FXa and PAR-2 are overexpressed and that specific FXa inhibition is beneficial. 37 Moreover, a recent clinical study shows that Dalteparin (a FXa inhibitor) administration improved the survival of IPF patients. 58 Because, to date, no PAR-2 antagonists are clinically available, the inhibition of FXa might be an interesting alternative therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

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Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Borensztajn

Bresser

Loos

et al. 2010

The American Journal of Pathology

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Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease-activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study. We show that PAR-2 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival. Using a bleomycin model of pulmonary fibrosis, we show that bleomycin induces PAR-2 expression, as well as both myofibroblast differentiation and collagen synthesis. In PAR-2؊/؊ mice, both the extent and severity of fibrotic lesions are reduced, whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover, fibrin deposition in the lungs of fibrotic PAR-2؊/؊ mice is reduced compared with wild-type mice due to differential tissue factor expression in response to bleomycin. Taken together , these results suggest an important role for PAR-2 in the development of pulmonary fibrosis , and the inhibition of the PAR-2-coagulation axis may provide a novel therapeutic approach to treat this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Borensztajn

Bresser

Loos

et al. 2010

The American Journal of Pathology

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“…PAR2 is activated by TF-coagulation factor VIIa complex and coagulation factor Xa (FXa) and upregulates inflammation and fibrosis through nuclear factor-kappa B (NF-κB) or mitogenactivated protein kinase (MAPK) signaling. [12][13][14] Although FXa and PAR2 are suggested to be responsible for the progression of kidney injury, [15][16][17][18] their role in DN is poorly understood.…”

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confidence: 99%

“…Biochemical measurements 16 Urinary albumin levels were determined using the Albuwell-M kit (Exocell Inc., Philadelphia,…”

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confidence: 99%

Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

Hayashi

Fushima

et al. 2016

ATVB

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Objective-The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation. Approach and Results-Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages. Administration of an oral FXa inhibitor, edoxaban, ameliorated DN with concomitant reductions in the expression of PARs (Par1 and Par2) and of proinflammatory and profibrotic genes. Diabetes mellitus induced PAR2, and lack of Par2 ameliorated DN. FXa or PAR2 agonist increased inflammatory cytokines in endothelial cells and podocytes in vitro. Conclusions-We conclude that enhanced FXa and PAR2 exacerbate DN and that both are promising targets for preventing DN. Alleviating inflammation is probably more important than inhibiting coagulation per se when treating kidney diseases using anticoagulants.

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“…14,15) We previously reported that the coagulation process proceeds together with the ECM accumulation through factor V expression in rat Thy-1 nephritis, 16) and that DX-9065a, a factor Xa inhibitor, suppresses this type of gomerulonephritis. 17) Because renal tissue factor expression and fibrin deposition are observed in streptozotocin-induced type 1 diabetic mice, 5,18) it is suspected that the coagulation process is activated through factor Xa formation in diabetic nephropathy. It has been reported that fondaparinux, a synthetic pentasaccharide that selectively inhibits factor Xa, reduces the inflammatory response in injured kidneys due to ischemia-reperfusion.…”

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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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Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Cited by 29 publications

References 44 publications

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

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

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