Renal
fibrosis is defined by excessive extracellular matrix (ECM) accumulation and is associated with a decreased kidney function. Increased
inflammation and infiltration of inflammatory cells are the key features of renal
fibrosis development; however, the mechanism of how
inflammation starts is still un-known. Here, we show that the activation of epithelial
Protease-activating receptor 2 (PAR2) signaling plays an important role in the initiation of
inflammation via increased
chemokine expression and inflammatory cell induction. In the
adenine diet-induced renal
fibrosis mouse model, PAR2 expression was significantly increased in the renal tubule region. Kidneys from PAR2-knockout mice were protected from
adenine diet-induced renal
fibrosis, kidney dysfunction, and
inflammation. Using NRK52E kidney epithelial cells, we further elucidated the mechanisms underlying these processes. Activation of PAR2 signaling pathway by PAR2 agonist specifically increased the levels of
chemokines, including MCP1 and MCP3, via the MAPK-NF-κB signaling pathway. Inhibition of the MAPK signaling pathway attenuated PAR2 agonist-induced NF-κB activation,
chemokine expression, and macrophage cell induction. Furthermore, PAR2 activation directly increased mesenchymal cell markers in epithelial cells. Taken together, we found that increased PAR2 expression and the PAR2/MAPK signaling pathway promote renal
fibrosis by increasing the inflammatory responses and promoting EMT process.