Vitamin E inhibits cyclosporin A-induced CTGF and TIMP-1 expression by repressing ROS-mediated activation of TGF-β/Smad signaling pathway in rat liver

Cyclosporin A (CsA) is the most common immunosuppressive drug used in organ transplantation. However, the clinical use of CsA is often limited by several side effects including hepatotoxicity. In the present study, it was found that administration of CsA causes a rapid activation of TGF-beta/Smad signaling cascade and subsequent expression of the profibrotic genes connective tissue growth factor (CTGF) and tissue inhibitors of matrix metallproteinases-1 (TIMP-1) in rat liver. In addition, Smad phosphorylation and subsequent CTGF and TIMP-1 expression were markedly reduced in the presence of neutralizing monoclonal TGF beta(1-3) antibody. Furthermore, CsA administration significantly increased the serum levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as lipid peroxidation in hepatic tissues. Moreover, significant reduction in the hepatic content of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) was observed in CsA-alone-treated animals. Histopathological changes were also observed in CsA-alone-treated rats. Pretreatment of animals with Vitamin E (Vit E) before CsA administration significantly reduced TGF-beta level as well as Smad phosphorylation and subsequent CTGF and TIMP-1 expression. Furthermore, administration of PEG-SOD clearly attenuated TGF-beta/Smad signaling induced by CsA. Moreover, concomitant administration of Vit E along with CsA significantly ameliorated the histopathological changes and improved liver function as well as the antioxidant capacity. Finally, this study shows that the immunosuppressive efficiency of CsA was not altered in the presence of Vit E. These data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA-induced tissue fibrosis.