Pharmacology · 2011
Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice.
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Wang Ling Hao, Liu Ji Shi, Ning Wang Bin, Yuan Qiong Jing, Zhang Fang Fang, Peng Zhang Zhe, Lu Miao Miao, Luo Ren Na, Fu Xiao, Hu Gao Yun, Wang Zhao He, Tao Li Jian
Аннотация
BACKGROUND/AIMS: Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD], a novel pyridone agent, showed potent antifibrotic properties. The aim of the present study was to investigate the effects of AKF-PD on diabetic nephropathy and kidney fibrosis, and to obtain an insight into its mechanisms of action.
METHODS: We administered AKF-PD to diabetic db/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine mesangial cells exposed to high ambient glucose concentrations.
RESULTS: AKF-PD reduced renal hypertrophy, mesangial matrix expansion and albuminuria in the db/db mice. The upregulated expression of α₁(I)- and α₁(IV)-collagen and fibronectin mRNAs, transforming growth factor-β1 (TGF-β₁), α-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase 1 (TIMP-1) mRNAs and proteins was inhibited by AKF-PD treatment in the renal cortex of db/db mice. The maximal effective dose of AKF-PD was about 500 mg/kg body weight. AKF-PD inhibited the upregulated expression of α₁(I)- and α₁(IV)-collagens, TGF-β₁, TIMP-1 and α-SMA induced by high glucose concentrations in cultured mesangial cells.
CONCLUSIONS: Our data indicate that AKF-PD diminishes the abnormal accumulation of mesangial matrix through the inhibition of upregulated expression of TGF-β target genes in kidneys of db/db mice, resulting in attenuation of renal fibrosis and amelioration of renal dysfunction despite persistent hyperglycemia. Therefore, AKF-PD, a potent antifibrotic agent, holds great promise in the treatment of diabetic nephropathy.
METHODS: We administered AKF-PD to diabetic db/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine mesangial cells exposed to high ambient glucose concentrations.
RESULTS: AKF-PD reduced renal hypertrophy, mesangial matrix expansion and albuminuria in the db/db mice. The upregulated expression of α₁(I)- and α₁(IV)-collagen and fibronectin mRNAs, transforming growth factor-β1 (TGF-β₁), α-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase 1 (TIMP-1) mRNAs and proteins was inhibited by AKF-PD treatment in the renal cortex of db/db mice. The maximal effective dose of AKF-PD was about 500 mg/kg body weight. AKF-PD inhibited the upregulated expression of α₁(I)- and α₁(IV)-collagens, TGF-β₁, TIMP-1 and α-SMA induced by high glucose concentrations in cultured mesangial cells.
CONCLUSIONS: Our data indicate that AKF-PD diminishes the abnormal accumulation of mesangial matrix through the inhibition of upregulated expression of TGF-β target genes in kidneys of db/db mice, resulting in attenuation of renal fibrosis and amelioration of renal dysfunction despite persistent hyperglycemia. Therefore, AKF-PD, a potent antifibrotic agent, holds great promise in the treatment of diabetic nephropathy.
Предметные рубрики MeSH
AlbuminsAnimalsBlood GlucoseCell Culture TechniquesCollagenDiabetes Mellitus, Type 2Diabetic NephropathiesDisease Models, AnimalDrug Evaluation, PreclinicalExtracellular MatrixFibronectinsFibrosisHyperglycemiaHypoglycemic AgentsKidneyKidney CortexKidney DiseasesMaleMiceMice, KnockoutPyridonesTransforming Growth Factor beta1