Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease

Shohei Mitsui, Yuji Oe, Akiyo Sekimoto, Emiko Sato, Yamato Hashizume, Shu Yamakage, Satoshi Kumakura, Hiroshi Sato, Sadayoshi Ito, Nobuyuki Takahashi

Research output: Contribution to journalArticlepeer-review

Abstract

Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg-1·day-1), PAR2 antagonist (FSLLRY, 3 mg·kg-1·day-1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 +FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-кB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-кB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.

Original languageEnglish
Pages (from-to)F1067-F1073
JournalAmerican Journal of Physiology - Renal Physiology
Volume318
Issue number5
DOIs
Publication statusPublished - 2020 May

Keywords

  • Coagulation
  • Cytokine
  • Endothelium
  • Fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease'. Together they form a unique fingerprint.

Cite this