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

Nephrology (Carlton). 2017 Aug;22(8):589-597. doi: 10.1111/nep.12831.


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.

Keywords: MAPK signalling pathway; epithelial-to-mesenchymal transition; pirfenidone; renal fibrosis.

MeSH terms

  • Actins / metabolism
  • Animals
  • Antigens, CD
  • Cadherins / metabolism
  • Cell Line
  • Collagen Type I / metabolism
  • Collagen Type III / metabolism
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kidney Diseases / enzymology
  • Kidney Diseases / etiology
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / pathology
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Pyridones / pharmacology*
  • Rats, Sprague-Dawley
  • Renal Agents / pharmacology*
  • S100 Calcium-Binding Protein A4 / metabolism
  • Transforming Growth Factor beta1 / metabolism
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / enzymology
  • Ureteral Obstruction / pathology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • ACTA2 protein, human
  • Actins
  • Antigens, CD
  • CDH1 protein, human
  • CDH1 protein, rat
  • Cadherins
  • Collagen Type I
  • Collagen Type III
  • Fibronectins
  • Pyridones
  • Renal Agents
  • S100 Calcium-Binding Protein A4
  • S100a4 protein, rat
  • TGFB1 protein, human
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • smooth muscle actin, rat
  • S100A4 protein, human
  • pirfenidone
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases