University of Khartoum

Activation of Smad-Dependent Signaling Pathways by the Mtor Inhibitor Sirolimus in Rat Glomerular Mesangial Cells

Activation of Smad-Dependent Signaling Pathways by the Mtor Inhibitor Sirolimus in Rat Glomerular Mesangial Cells

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Title: Activation of Smad-Dependent Signaling Pathways by the Mtor Inhibitor Sirolimus in Rat Glomerular Mesangial Cells
Author: Osman, Bashier Ibrahim; Doller, A.; Akool, E.S.; Eberhardt, Wolfgang
Abstract: Activation of smad-dependent signaling pathways by the mTOR inhibitor sirolimus in rat glomerular mesangial cells Osman B., Doller A., Akool E.S., Pfeilschifter J., Eberhardt W. The mTOR kinase inhibitor Sirolimus is a drug with potent immunosuppressive and antiproliferative properties. In transplantation medicine Sirolimus is often used in combination with the calcineurin inhibitors (CNIs) ciclosporin A (CsA) and tacrolimus (FK506) in order to limit their high nephrotoxic side effects. These side effects are mainly characterized by a strong tubular atrophy accompanied by interstitial and glomerular fibrosis. We previously have shown that CNIs cause a rapid activation of the TGFb-Smad signaling cascade in rat glomerular mesangial cells thereby activating the expression of prominent profibrotic genes such as tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) and plasminogenactivator inhibitor-1 (PAI-1). In the present study, we demonstrate that Sirolimus in a dose-dependent manner, similar to CNIs, can cause a rapid activation of the Smad-signaling cascade as indicated by a rapid increase in the nuclear contents of phosphorylated Smad proteins Smad-2 and Smad-3 and accompanied by an increased DNA-binding of both transcription factors to a cognate Smad-binding promoter element (SBE). Mechanistically, the activation of R-Smads by Sirolimus depends on a rapid activation of latent TGFb and type I-and IITGFb-receptors as demonstrated by neutralizing TGFb-strategies and by RNA interference. Interestingly, the Sirolimus-induced Smad signaling is strongly impaired by SB203580 indicating an additional involvement of the p38 MAP-kinase. Conversely, the activation of p38 by Sirolimus is affected by an inhibitor of the TGFb- receptor-I kinase thus demonstrating functional cross-talk of both different signaling pathways. Functionally, the Sirolimus-caused Smad activation leads to a significant increase in the transcriptional activity of TGFb -inducible genes CTGF and PAI-1. Finally, we found a critical involvement of reactive oxygen species (ROS) in both, p38 activation and TGFb activation since ROS scavengers strongly impaired both of these processes. Collectively, our data demonstrate that Sirolimus by release of TGFb propagates a rapid induction of the Smad signaling thereby accelerating the expression of profibrotic genes. Pharmacenter Frankfurt, Hospital of the Johann Goethe University , Frankfurt
URI: http://khartoumspace.uofk.edu/123456789/24777


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