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.

CONCLUSION:

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: Qiongjing Yuan, Rui Wang, Yu Peng, Xiao Fu, Wei Wang, Linghao Wang, Fangfang Zhang, Zhangzhe Peng, Wangbin Ning, Gaoyun Hu, Zhaohe Wang, Lijian Tao
• Journal: American journal of nephrology (Am J Nephrol) Vol. 34 Issue 2 Pg. 181-94 ( 2011) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 21791914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 S. Karger AG, Basel.

Chemical References

• 5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone
• Pyridones
• Smad Proteins
• Transforming Growth Factor beta1
• MAP Kinase Kinase 4

Topics

• Animals
• Body Weight
• Fibroblasts (metabolism)
• Fibrosis (drug therapy)
• Gene Expression Regulation
• Kidney (metabolism)
• Kidney Tubules (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Male
• Phosphorylation
• Pyridones (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Smad Proteins (metabolism)
• Transforming Growth Factor beta1 (metabolism)