No 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-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB 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.

No abstract

The neuropeptide oxytocin plays a central role in prosocial and parental behavior in non-human mammals as well as humans. It has been suggested that oxytocin may affect visual processing of infant faces and emotional reaction to infants. Healthy male volunteers (N = 13) were tested for their ability to detect infant or adult faces among adult or infant faces (facial visual search task). Urine samples were collected from all participants before the study to measure the concentration of oxytocin. Urinary oxytocin positively correlated with performance in the facial visual search task. However, task performance and its correlation with oxytocin concentration did not differ between infant faces and adult faces. Our data suggests that endogenous oxytocin is related to facial visual cognition, but does not promote infant-specific responses in unmarried men who are not fathers.