Pirfenidone suppresses MAPK signalling pathway to reverse epithelial‐mesenchymal transition and renal fibrosis

Abstract Aim Recent studies indicate that pirfenidone (PFD) may have anti‐fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial‐to‐mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK‐2). Methods Sixty rats were randomly divided into three groups: sham‐operated, vehicle‐treated UUO, and PFD‐treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK‐2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, α‐SMA, S100A4, fibronection and E‐cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c‐Jun N‐terminal kinase/stress‐activated protein kinase (JNK) were also detected. Results In vitro, PFD significantly attenuated TGF‐β1‐induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of α‐SMA, type I and III collagen, S100A4, fibronection, and increased expression of E‐cadherin. PFD treatment attenuated TGF‐β1‐induced up‐regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF‐β1, type III collagen, α‐SMA, S100A4, fibronection, and increased expression of E‐cadherin. Conclusion These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis.