title: Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Pathological Experiment Center, Henan University of Traditional Chinese Medicine, Zhengzhou, China.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Pharmacology and Toxicology Experiment Center, Pharmacology Department, Henan University of Traditional Chinese Medicine, Zhengzhou, China.
authors.forename: Baoying
authors.initials: B
authors.lastname: Wang
authors.affiliation: Pharmacology Department, School of Medicine, Zhengzhou University, Zhengzhou, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.affiliation: Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Gu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000494:pharmacology*; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D024042:Collagen Type I; D024061:Collagen Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D005353:Fibronectins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D011728:Pyridones; D012076:Renal Agents; D000071999:S100 Calcium-Binding Protein A4; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; C541116:ACTA2 protein, human; C513384:CDH1 protein, human; C000610228:CDH1 protein, rat; C499412:S100a4 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat; C077591:S100A4 protein, human; C093844:pirfenidone
keywords: MAPK signalling pathway; epithelial-to-mesenchymal transition; pirfenidone; renal fibrosis