Vitamin E (Alpha Tocopherol) ameliorates renal fibrosis in ureteral obstruction : role of inhibiting TGF-β/SMAD signal induced epithelial-to-mesenchymal transition

Abstract

Epithelial-to-mesenchymal transition (EMT) is the most important mechanism that induces the progression of renal fibrosis. Transforming growth factor-β (TGF-β) superfamily/Smad signal transduction plays the critical roles during inflammatory process in EMT. Vitamin E (alpha tocopherol) is demonstrated to be anti-oxidant and anti-inflammatory property. So, the anti-inflammatory effect of vitamin E was examined in this study to against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction (UUO) and (2) the TGF-β superfamily/Smad signal transduction induced EMT. UUO or sham operation was induced in ICR mice and vitamin E (250mg/kgBW) or vehicle was administrated orally everyday from 5 day before until day 14 post operation. Mice were sacrificed at day 3, 7 and 14 after operation. Histopathology, TGF-β superfamily/Smad signals and mesenchymal markers were evaluated by immunohistochemical staining, western blot analysis and real time RT-PCR. Compared with sham group, H&E and Masson trichrome staining showed the progression of tubular atrophy and interstitial fibrosis (TA/IF) in UUO with vehicle treatment group. However, vitamin E treatment significantly ameliorated the TA/IF when compared with vehicle treatment. From protein and mRNA analysis revealed the increased expression of S100A4 that consequently from increased TGF-β1 and Smad2/3 but decreased expression of BMP-7 and Smad1/5/8 in the obstructed kidneys. In contrast, vitamin E treatment significantly inhibited the expression of S100A4, TGF-β1 and Smad 2/3 but maintained the expression of BMP-7 and Smad 1/5/8. In conclusion, vitamin E treatment ameliorated the progression of renal fibrosis in obstructed kidneys by inhibited TGF-β1 and Smad2/3 but maintained BMP-7 and Smad1/5/8 during EMT. Thus, the renoprotective effect of vitamin E could have therapeutic value in humans to inhibit the progression of renal fibrosis.