WHEAT GERM OIL AND VITAMIN E INHIBIT TGF-β/SMAD SIGNALING PATHWAY INDUCED BY TACROLIMUS (FK506) IN RAT KIDNEY

Abstract

Tacrolimus (FK506) is one of the most important immunosuppressive agents used in organ transplantation. However, its clinical use is strongly limited due to its nephrotoxicity. Transforming growth factor-b (TGF-b) and downstream Smad signaling have been found to play an important role in renal fibrosis via induction of profibrotic genes such as connective tissue growth factor (CTGF) and tissue inhibitors of matrix metallproteinases-1 (TIMP-1). FK506 has been shown to activate TGF-b/Smad signaling pathway in ROS dependent manner.  The present work was designed to test the potential modulatory effect of wheat germ oil (WGO) as well as Vitamin E (Vit E) on TGF-b/Smad signaling pathway and subsequent CTGF and TIMP-1 expression induced by FK506 in rat kidney. It was found that FK506 administration causes a rapid activation of TGF-b/Smad signaling pathway as indicated by an increase in plasma TGFb level and Smad-2 phosphorylation. In addition, activation of TGF-b/Smad signaling cascade is accompanied by an increase in Smad-dependent expression of CTGF and TIMP-1. Interestingly, concomitant administration of WGO as well as Vit E along with FK506 markedly inhibits TGF-b/Smad signaling pathway and subsequent CTGF and TIMP-1 expression that were associated with an increase in superoxide dismutase activity. Moreover, the immunosuppressive efficiency of FK506 neither affected by WGO nor Vit E.