Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis

• DOI: 10.1074/jbc.m113.492793
• Publication Date: 2013-11-20T02:59:19Z
• Authors: Hyunjae Chung; Rithwik Ramachandran; Morley D. Hollenberg; Daniel A. Muruve
• Keywords: Male; Transcriptional Activation; 0301 basic medicine; 570; Connective Tissue Growth Factor; 610; Smad2 Protein; Fibrosis; Mice, Mutant Strains; 3. Good health; ErbB Receptors; Kidney Tubules, Proximal; Mice; 03 medical and health sciences; Animals; Humans; Receptor, PAR-2; Female; Kidney Diseases; Smad3 Protein; Oligopeptides; Receptors, Transforming Growth Factor beta; Cells, Cultured; Signal Transduction

Chronic kidney diseases cause significant morbidity and mortality in the population. During renal injury, kidney-localized proteinases can signal by cleaving activating proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor involved inflammation fibrosis that is highly expressed tubular cells. Following unilateral ureteric obstruction, PAR2-deficient mice displayed reduced fibrosis, collagen synthesis, connective tissue growth factor (CTGF), α-smooth muscle actin gene expression at 7 days, compared with wild-type controls. In human proximal epithelial cells vitro, PAR2 stimulation PAR2-activating peptide (PAR2-AP) alone significantly up-regulated of CTGF, potent profibrotic cytokine. The induction CTGF PAR2-AP was synergistically increased when combined transforming factor-β (TGF-β). Consistent these findings, treating induced Smad2/3 phosphorylation canonical TGF-β signaling pathway. Smad2 required via both TGFβ-receptor EGF suggesting utilizes transactivation mechanisms to initiate fibrogenic signaling. Taken together, our data support hypothesis synergizes TGFβ pathway contribute injury fibrosis.