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  • Title: Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation.
    Author: Yuan Q, Wang R, Peng Y, Fu X, Wang W, Wang L, Zhang F, Peng Z, Ning W, Hu G, Wang Z, Tao L.
    Journal: Am J Nephrol; 2011; 34(2):181-94. PubMed ID: 21791914.
    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.
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