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

Oe, Yuji; Hayashi, Sakiko; Fushima, Tomofumi; Sato, Emiko; Kisu, Kazuaki; Sato, Hiroshi; Ito, Sadayoshi; Takahashi, Nobuyuki

doi:10.1161/atvbaha.116.307883

Cited by 78 publications

(113 citation statements)

References 49 publications

(74 reference statements)

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“…16 FXa stimulates proteaseactivated receptor 2 (PAR2). 17 The activation of PAR2 promotes pro-inflammatory activation of macrophages, as determined by inflammatory molecule expression and foam cell formation, which promotes vascular inflammation. 18 The direct thrombin inhibitor also inhibits the expression of pro-inflammatory markers.…”

Section: Anti-inflammatory Effect Of Doacmentioning

confidence: 99%

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients

Hamanaka

Sotomi

Hirata

et al. 2020

Circ J

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risk in non-valvular AF (NVAF) patients treated with direct oral anticoagulants (DOAC). Methods Subjects We conducted a single-center prospective observational registry of NVAF patients with DOAC: Safety and effectiveness of 4 Different dIrect oRal anticoagulants, dabigatran, rivaroxaban, apixaban and edoxaban in rEal-world Clinical pracTice (DIRECT registry; UMIN000033283). All serial adult patients (aged ≥18 years) at Osaka Police Hospital with NVAF who were users of dabigatran, rivaroxaban, apixaban, or edoxaban from June 2011 to November 2017 were enrolled. If a patient ever used DOAC during I n daily clinical practice, bleeding risk assessment in patients with atrial fibrillation (AF) is of paramount importance, given that bleeding events in patients with cardiovascular disease can be life-threatening. 1-5 In order to assess the bleeding risk precisely and objectively, we can use the bleeding risk assessment scores, ORBIT or HAS-BLED scores. 2,4,6 The previously reported bleeding risk factors are older age, anemia, bleeding history, insufficient kidney function, treatment with antiplatelets, hypertension, stroke, labile international normalized ratio and so on. 2,4 No factors associated with systemic inflammation have been reported to date. Several studies, however, suggested that systemic inflammation could play a critical role in the subsequent cardiovascular events, 7-9 therefore it is highly possible that activation of systemic inflammatory status could predict subsequent bleeding events. The purpose of the present study was to investigate the impact of systemic inflammation on subsequent bleeding Editorial p 376

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Section: Anti-inflammatory Effect Of Doacmentioning

confidence: 99%

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients

Hamanaka

Sotomi

Hirata

et al. 2020

Circ J

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“…Furthermore, cross-talk occurs between PAR1/2 signaling and TGF-β signaling, which links to tissue fibrosis [31,32]. PAR1/2 deficiency has been reported to be protective against experimental renal ischemia-reperfusion injury [33], crescentic GN [34], diabetic nephropathy [35,36], and unilateral ureteral obstruction [37,38]. TM reportedly plays a role in PAR activation, with thrombin no longer converting fibrinogen to fibrin or activating PAR1 when it binds to the EGF-like domains of TM [1].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats

Kanazawa

Iyoda

Tachibana

et al. 2020

Kidney Blood Press Res

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Background: Recombinant human soluble thrombomodulin (rhTM) was approved in 2008 and has been used for treatment of disseminated intravascular coagulation in Japan. The antifibrotic effects of rhTM in acute exacerbation of idiopathic pulmonary fibrosis are well established, but the therapeutic potential of rhTM in renal fibrosis remains poorly understood. Methods: Nephrotoxic serum nephritis (NTS-N) was induced in 22 female Wistar-Kyoto (WKY) rats on day 0. Rats were administered either rhTM or vehicle intraperitoneally, every day from day 4 to day 55. Rats were sacrificed on day 56 when renal fibrosis was established and renal morphological investigations were performed. In vitro, rat renal fibroblasts (NRK-49F) were pretreated with rhTM or saline, and expression levels of profibrogenic gene induced by thrombin were analyzed by real-time reverse transcription polymerase chain reaction. Results: Compared to WKY-GN-vehicle rats, the body weights of WKY-GN-rhTM rats were significantly greater on day 55. By day 56, rhTM had significantly reduced serum creatinine levels in NTS-N. On the other hand, urinary protein excretion was comparable between the two treatment groups throughout the study. The percentage of Masson trichrome-positive areas in WKY-GN-rhTM rats was significantly lower compared to that in WKY-GN-vehicle rats. Glomerular fibrin deposition was significantly reduced in WKY-GN-rhTM rats. In addition, rhTM significantly reduced the renal cortical mRNA expression levels of TNF-α, Toll-like receptor 4, MYD88, TGF-β, αSMA, collagen I, collagen III, fibronectin, and protease-activated receptor 1

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“…PAR2 increases cytokine or chemokine production through mitogen-activated protein kinase or nuclear factor kappa B signaling (Rothmeier and Ruf 2012;Vesey et al 2013). In murine kidney disease models, genetic deletion or pharmacological inhibition of PAR2 improves diabetic kidney disease (DKD), glomerulonephritis, renal fibrosis, and cisplatin nephrotoxicity through inflammatory cytokine or profibrotic mediator reduction (Moussa et al 2007;Kumar Vr et al 2016;Oe et al 2016;Hayashi et al 2017;Watanabe et al 2019). On the other hand, in a recent study, we demonstrated that a deficiency of PAR2 aggravates vascular endothelial growth factor inhibitor-induced glomerular injury (Oe et al 2019).…”

Section: Introductionmentioning

confidence: 94%

“…at 95℃ for 5s and annealing and extension at 60℃ for 15s. We have published the primer sequences in our previous reports (Li et al 2010;Oe et al 2016).…”

Section: Quantitative Real-time Polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

“…Studies using several different murine models of kidney injury have shown that there is an increase in the renal expression of PAR1 and PAR2 (Oe et al 2016;Hayashi et al 2017;Watanabe et al 2019); thus, in this study, we measured the renal expression levels of Par1 and Par2 mRNA. The expression levels of Par1 mRNA were similar among MRL/+, MRL/lpr-saline, and MRL/lpr-FSLLRY-NH2 mice (Fig.…”

Section: Renal Expression Of Par2 Mrna In Sle-prone Micementioning

confidence: 99%

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Glomerular Injury Is Exacerbated in Lupus-Prone MRL/lpr Mice Treated with a Protease-Activated Receptor 2 Antagonist

Itto

Imaruoka

et al. 2019

Tohoku J. Exp. Med.

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Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies, which causes multi-organ injury such as lupus nephritis. SLE is associated with hypercoagulability. Activated coagulation factors such as tissue factor and VIIa complex and factor Xa activate protease-activated receptor 2 (PAR2). PAR2 promotes cytokine production through mitogen-activated protein kinase or nuclear factor kappa B signaling, and previous reports demonstrated that inhibition of PAR2 alleviated kidney injuries such as diabetic kidney disease and renal fibrosis in animal models. However, the involvement of PAR2 in the pathogenesis of SLE remains unclear. We therefore administered a selective PAR2 peptide antagonist, FSLLRY-NH2, to SLE-prone 4-month-old MRL-Fas lpr mice for 4 weeks. Treatment with FSLLRY-NH2 caused the significant increases in the glomerular mesangial proliferation, glomerular deposition of both immunoglobulin G and complement factor C3d, and glomerular infiltration of Mac2-positive macrophages and CD3-positive T cells, compared with MRL-Fas lpr mice treated with saline. In addition, the treatment with the PAR2 antagonist increased renal expression levels of tumor necrosis factor-α (Tnfa) and monocyte chemoattractant protein 1 (Mcp1) mRNA. Collectively, these results suggest that inhibition of PAR2 may increase the severity of inflammation in lupus nephritis; namely, opposite to previous observations, PAR2 has anti-inflammatory properties. We propose that activation of PAR2 could serve as a potential therapeutic option for patients with SLE.

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

Cited by 78 publications

References 49 publications

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients

Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats

Glomerular Injury Is Exacerbated in Lupus-Prone MRL/lpr Mice Treated with a Protease-Activated Receptor 2 Antagonist

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