title: Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation.
abstract: BACKGROUND
  Novel therapeutic agents are urgently needed to combat renal fibrosis. The purpose of this study was to assess, using complete unilateral ureteral obstruction (UUO) in rats, whether fluorofenidone (AKF-PD) [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone] inhibits renal fibrosis, and to determine whether it exerts its inhibitory function on renal fibroblast activation.
  
  
  METHODS
  Sprague-Dawley rats were randomly divided into 3 groups: sham operation, UUO and UUO/AKF-PD (500 mg/kg/day). Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF-β(1), collagen III, α-SMA, p-Smad2, p-Smad3, p-ERK1/2, p-JNK and p-p38 were measured. In addition, the expressions of α-SMA, fibronectin, CTGF, p-Smad2/3, p-ERK1/2, p-p38 and p-JNK were measured in TGF-β(1)-stimulated normal rat renal fibroblasts (NRK-49F).
  
  
  RESULTS
  AKF-PD treatment significantly attenuated tubulointerstitium damage, ECM deposition, the expressions of TGF-β(1), collagen III, α-SMA, p-ERK1/2, p-p38 and p-JNK in vivo. In vitro, AKF-PD dose-dependently inhibited expressions of α-SMA, fibronectin and CTGF. Furthermore, AKF-PD did not inhibit Smad2/3 phosphorylation or nuclear accumulation, but rather attenuated ERK, p38 and JNK activation.
  
  
  CONCLUSIONS
  AKF-PD treatment inhibits the progression of renal interstitial fibrosis in obstructed kidneys; this is potentially achieved by suppressing fibroblast activation. Therefore, AKF-PD is a special candidate for the treatment of renal fibrosis.
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Qiongjing
authors.initials: Q
authors.lastname: Yuan
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.forename: Xiao
authors.initials: X
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Linghao
authors.initials: L
authors.lastname: Wang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhang
authors.forename: Zhangzhe
authors.initials: Z
authors.lastname: Peng
authors.forename: Wangbin
authors.initials: W
authors.lastname: Ning
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.forename: Zhaohe
authors.initials: Z
authors.lastname: Wang
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D001835:Body Weight; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000188:drug therapy*; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D011728:Pyridones; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D048670:MAP Kinase Kinase 4