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

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Protease-activated receptors (PARs) are implicated in inflammatory cytokine and chemokine expression in various diseases.
• Previous studies indicate PAR1 or PAR2 inhibition offers protection against diabetic glomerular injury.
• The cooperative role of PAR1 and PAR2 in diabetic kidney disease (DKD) pathogenesis and the efficacy of dual blockade remain unclear.

Purpose of the Study:

• To investigate the cooperative contribution of PAR1 and PAR2 to DKD pathogenesis.
• To evaluate the therapeutic efficacy of dual blockade of PAR1 and PAR2 in a mouse model of DKD.

Main Methods:

• Male type I diabetic Akita mice were treated with vehicle, PAR1 antagonist (E5555), PAR2 antagonist (FSLLRY), or dual PAR1/PAR2 antagonists for 4 weeks.
• Assessment included urinary albumin-to-creatinine ratio, kidney histology (mesangial expansion, macrophage infiltration, collagen IV deposition), and gene expression analysis.
• In vitro studies used human endothelial cells treated with PAR1/PAR2 agonists and inhibitors (NF-κB, MAPK).

Main Results:

• Dual blockade of PAR1 and PAR2 significantly reduced albuminuria and ameliorated histological damage, including mesangial expansion and inflammatory cell infiltration.
• Combined inhibition additively reduced kidney expression of inflammation- and fibrosis-related genes.
• In vitro, PAR1 and PAR2 agonists synergistically increased pro-inflammatory gene expression, with distinct signaling pathways (NF-κB for PAR1; MAPK/NF-κB for PAR2).

Conclusions:

• PAR1 and PAR2 additively contribute to the pathogenesis of diabetic kidney disease.
• Dual blockade of PAR1 and PAR2 demonstrates significant therapeutic potential in ameliorating DKD.
• Combined PAR1 and PAR2 inhibition represents a novel therapeutic strategy for patients with DKD.