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

Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease. Am J Physiol Renal Physiol. 2020 Mar 23;: Authors: Mitsui S, Oe Y, Sekimoto A, Sato E, Hashizume Y, Yamakage S, Kumakura S, Sato H, Ito S, Takahashi N 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 show that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to DKD pathogenesis and whether dual blockade of PARs is more effective in DKD remains elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Four month-old mice were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg/kg/d), PAR2 antagonist (FSLLRY, 3 mg/kg/d), or E5555+FSLLRY for 4 weeks. The results showed the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555+FSLLRY compared to the vehicle group. Dual blockade of PAR1 and PAR2 by E5555+FSLLRY additively ameliorated histological injury including mesangial expansion, glomerular macrophage infiltration, and collagen IV deposition. Marked reduction of inflammation and fibrosis-related gene expression in the kidney was also obs...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research