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

AimRecent 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). MethodsSixty 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, -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. ResultsIn vitro, PFD significantly attenuated TGF-1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of -SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-1-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-1, type III collagen, -SMA, S100A4, fibronection, and increased expression of E-cadherin. ConclusionThese 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. Summary at a Glance This study demonstrated the efficacy of the pirfenidone to improve renal fibrosis in both an experimental rodent model, UUO and on epithelial-to-mesenchymal transition and fibrotic markers in cultured human proximal tubular cells. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis. Hence pirfenidone could be further investigated as a potential treatment to alleviate renal tubulointerstitial fibrosis.