Proteinase-activated receptor-2 transactivation of epidermal growth factor receptor and transforming growth factor-β...

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Chronic kidney diseases present a significant global health burden.
• Kidney-localized proteinases activate proteinase-activated receptor-2 (PAR2), a receptor involved in renal inflammation and fibrosis.
• PAR2 is highly expressed in renal tubular cells, suggesting a key role in kidney injury.

Purpose of the Study:

• To investigate the role of PAR2 in renal injury and fibrosis.
• To elucidate the signaling mechanisms by which PAR2 contributes to kidney disease progression.

Main Methods:

• Utilized PAR2-deficient mice subjected to unilateral ureteric obstruction.
• Examined renal tubular injury, fibrosis markers, and gene expression.
• Investigated PAR2 signaling in human proximal tubular epithelial cells in vitro using PAR2-activating peptide (PAR2-AP).
• Analyzed the interplay between PAR2, transforming growth factor-β (TGF-β), and epidermal growth factor receptor (EGFR) signaling pathways.

Main Results:

• PAR2-deficient mice showed reduced renal tubular injury, fibrosis, and associated gene expression following ureteric obstruction.
• PAR2 stimulation in human proximal tubular epithelial cells upregulated connective tissue growth factor (CTGF), a profibrotic cytokine.
• PAR2-AP synergistically enhanced TGF-β-induced CTGF expression and induced Smad2/3 phosphorylation.
• PAR2-mediated CTGF induction and Smad2 phosphorylation required signaling through both TGF-β and EGF receptors.

Conclusions:

• PAR2 plays a critical role in mediating renal injury and fibrosis.
• PAR2 synergizes with the TGF-β signaling pathway, potentially via transactivation mechanisms involving EGFR, to promote fibrogenic signaling in the kidney.
• Targeting PAR2 may represent a therapeutic strategy for mitigating kidney fibrosis and disease progression.