Tranilast prevents the progression of chronic cyclosporine nephrotoxicity through regulation of transforming growth factor beta/Smad pathways.

摘要

PURPOSE: Our aim was to investigate the role of tranilast in transforming growth factor (TGF) beta/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-beta1 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-beta1 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-beta1: 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). CONCLUSION: Regulation of TGF-beta/Smad pathways is one of the mechanisims by which tranilast mitigates the progression of chronic CsA nephrotoxicity in rats.