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

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

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1525-1533
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number8
DOIs
Publication statusPublished - 2016 Aug 1

Keywords

  • cardiovascular diseases
  • diabetic nephropathy
  • factor Xa
  • inflammation
  • prognosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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