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

• Published in: The Journal of biological chemistry Vol. 288; no. 52; pp. 37319 - 37331
• Main Authors: Chung, Hyunjae, Ramachandran, Rithwik, Hollenberg, Morley D., Muruve, Daniel A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.12.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cells, Cultured; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Epidermal Growth Factor Receptor (EGFR); ErbB Receptors - biosynthesis; ErbB Receptors - genetics; Female; Fibrosis; Fibrosis - metabolism; Fibrosis - pathology; Humans; Kidney; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Male; Mice; Mice, Mutant Strains; Molecular Bases of Disease; Oligopeptides - pharmacology; PAR2; Receptor, PAR-2 - agonists; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Receptors; Receptors, Transforming Growth Factor beta - biosynthesis; Receptors, Transforming Growth Factor beta - genetics; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Transcriptional Activation; Transforming Growth Factor β (TGFβ); Receptors; PAR2; Transforming Growth Factor β (TGFβ); Epidermal Growth Factor Receptor (EGFR); Kidney; Fibrosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.492793

Chronic kidney diseases cause significant morbidity and mortality in the population. During renal injury, kidney-localized proteinases can signal by cleaving and activating proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor involved in inflammation and fibrosis that is highly expressed in renal tubular cells. Following unilateral ureteric obstruction, PAR2-deficient mice displayed reduced renal tubular injury, fibrosis, collagen synthesis, connective tissue growth factor (CTGF), and α-smooth muscle actin gene expression at 7 days, compared with wild-type controls. In human proximal tubular epithelial cells in vitro, PAR2 stimulation with PAR2-activating peptide (PAR2-AP) alone significantly up-regulated the expression of CTGF, a potent profibrotic cytokine. The induction of CTGF by PAR2-AP was synergistically increased when combined with transforming growth factor-β (TGF-β). Consistent with these findings, treating human proximal tubular epithelial cells with PAR2-AP induced Smad2/3 phosphorylation in the canonical TGF-β signaling pathway. The Smad2 phosphorylation and CTGF induction required signaling via both the TGFβ-receptor and EGF receptor suggesting that PAR2 utilizes transactivation mechanisms to initiate fibrogenic signaling. Taken together, our data support the hypothesis that PAR2 synergizes with the TGFβ signaling pathway to contribute to renal injury and fibrosis. Background: The role for proteinase-activated receptor (PAR)-2 in the pathogenesis of renal fibrosis is not previously described. Results: PAR2−/− mice displayed attenuated renal fibrosis in vivo. PAR2 transactivation of EGF and TGFβ receptor signaling pathways induced Smad2 phosphorylation and connective tissue growth factor gene expression. Conclusion: PAR2 activation results in profibrotic signaling and gene expression. Significance: PAR2 represents a potential therapeutic target for chronic kidney disease.