Glomerular injury is exacerbated in lupus-prone MRL/lpr mice treated with a protease-activated receptor 2 antagonist

Rina Itto, Yuji Oe, Kenta Imaruoka, Emiko Sato, Akiyo Sekimoto, Shu Yamakage, Satoshi Kumakura, Hiroshi Sato, Sadayoshi Ito, Nobuyuki Takahashi

Research output: Contribution to journalArticlepeer-review

Abstract

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-Faslpr 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-Faslpr 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.

Original languageEnglish
Pages (from-to)127-133
Number of pages7
JournalTohoku Journal of Experimental Medicine
Volume249
Issue number2
DOIs
Publication statusPublished - 2019

Keywords

  • Coagulation factor
  • Complement factor
  • Cytokine
  • Lupus nephritis
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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