title: Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ling Hao
authors.initials: LH
authors.lastname: Wang
authors.forename: Ji Shi
authors.initials: JS
authors.lastname: Liu
authors.forename: Wang Bin
authors.initials: WB
authors.lastname: Ning
authors.forename: Qiong Jing
authors.initials: QJ
authors.lastname: Yuan
authors.forename: Fang Fang
authors.initials: FF
authors.lastname: Zhang
authors.forename: Zhang Zhe
authors.initials: ZZ
authors.lastname: Peng
authors.forename: Miao Miao
authors.initials: MM
authors.lastname: Lu
authors.forename: Ren Na
authors.initials: RN
authors.lastname: Luo
authors.forename: Xiao
authors.initials: X
authors.lastname: Fu
authors.forename: Gao Yun
authors.initials: GY
authors.lastname: Hu
authors.forename: Zhao He
authors.initials: ZH
authors.lastname: Wang
authors.forename: Li Jian
authors.initials: LJ
authors.lastname: Tao
mesh_terms: D000418:Albumins / Q000032:analysis; D000818:Animals; D001786:Blood Glucose; D018929:Cell Culture Techniques; D003094:Collagen / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000502:physiology; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007672:Kidney Cortex / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000418:Albumins; D001786:Blood Glucose; D005353:Fibronectins; D007004:Hypoglycemic Agents; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D003094:Collagen