title: Tranilast prevents the progression of chronic cyclosporine nephrotoxicity through regulation of transforming growth factor β/Smad pathways.
abstract: OBJECTIVE
  Our aim was to investigate the role of tranilast in transforming growth factor (TGF) β/Smad pathways using a rat model of chronic cyclosporine (CsA) nephrotoxicity.
  
  
  METHODS
  Thirty Sprague-Dawley (SD) rats were equally randomized in to 5 groups for gavage treatments daily for 4 weeks: normal control (N), olive oil; CsA (25 mg/kg), (M) CsA plus low-dose tranilast group (T1; CsA 25 mg/kg and tranilast 100 mg/kg); CsA plus medium-dose tranilast group (T2; CsA 25 mg/kg and tranilast 200 mg/kg); and CsA plus high-dose tranilast group (T4; CsA 25 mg/kg and tranilast 400 mg/kg). Kidneys were harvested at the end of the fourth week. TGF-β1 as well as Smad3 and Smad7 were detected by reverse-transcription polymerase chain reaction and immunohistochemistry.
  
  
  RESULTS
  The administration of tranilast decreased the expression of TGF-β1 and Smad3 by CsA-treated rats, whereas it increased both mRNA and protein levels of Smad7. Semiquantitative analysis of mRNA production revealed these treatments to markedly reduce the amount of TGF-β1: T1: 0.8452 ± 0.0825 vs 0.8529 ± 0.0606 (P < .05); T2: 0.8414 ± 0.0696 vs 0.8529 ± 0.0606 (P < .05); T4: 0.8336 ± 0.0592 vs 0.8529 ± 0.0606 (P < .05). For Smad3: T1: 0.8581 ± 0.0328 vs 0.8613 ± 0.0542 (P < .05); T2: 0.8528 ± 0.0599 vs 0.8613 ± 0.0542 (P < .05); T4: 0.8436 ± 0.0185 vs 0.8613 ± 0.0542 (P < .05). The significantly elevated dose-dependent amounts of Smad7 were: T1: 0.9026 ± 0.0522 vs 0.8678 ± 0.0246, (P < .05); T2: 0.9087 ± 0.0506 vs 0.8678 ± 0.0246 (P < .05); T4: 0.9151 ± 0.0793 vs 0.8678 ± 0.0246 (P < .05).
  
  
  CONCLUSIONS
  Regulation of TGF-β/Smad pathways is one of the mechanisims by which tranilast mitigates the progression of chronic CsA nephrotoxicity in rats.
authors.affiliation: Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.forename: L
authors.initials: L
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: P
authors.initials: P
authors.lastname: Fu
authors.forename: D
authors.initials: D
authors.lastname: Wei
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
mesh_terms: D000818:Animals; D001483:Base Sequence; D016572:Cyclosporine / Q000633:toxicity*; D017931:DNA Primers; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D007166:Immunosuppressive Agents; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D016572:Cyclosporine; C012293:tranilast