Dual blockade of protease-activated receptor 1 and 2 additively ameliorates
diabetic kidney disease.
Authors Mitsui S, Oe Y, Sekimoto A, Sato E, Hashizume Y, Yamakage S, Kumakura S, Sato H,
Ito S, Takahashi N
Submitted By Nobuyuki Takahashi on 11/20/2020
Status Published
Journal American journal of physiology. Renal physiology
Year 2020
Date Published 5/1/2020
Volume : Pages 318 : F1067 - F1073
PubMed Reference 32200667
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-?B inhibitor, whereas those of the PAR2 agonist were blocked by
MAPK and/or NF-?B 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.