TGFβ- and Bleomycin-Induced Extracellular Matrix Synthesis is Mediated Through Akt and Mammalian Target of Rapamycin (mTOR)

A number of pro-fibrogenic stimuli, such as growth factors, cytokines, and extracellular matrix (ECM) proteins, involve Akt and its downstream substrates in mediating their effects. We previously reported that absence of Akt1, which is the predominant isoform of the three gene Akt family in vascular cells, resulted in impaired ECM remodeling in skin and vasculature. In the current study, we investigated the importance of Akt1 in TGF beta- and bleomycin-induced synthesis and secretion of ECM proteins by fibroblasts. We observed that both TGF beta and bleomycin stimulated the synthesis of ECM proteins in a dose-and time-dependent manner. Treatment with TGF beta and bleomycin also resulted in increased phosphorylation of Akt, mammalian target of rapamycin (mTOR) and their downstream signaling partners, p70S6 Kinase, Ribosomal S6 protein and 4E-BP1, resulting in the activation of this pathway. The effects of TGF beta and bleomycin on ECM synthesis were blunted by pre-treatment with an mTOR inhibitor rapamycin. Whereas mTOR is responsible for the transcriptional regulation of a number of ECM proteins, adhesion molecules and matrix metalloproteases (MMPs), synthesis of major ECM proteins such as fibronectin and collagens (types I, II and V) by fibroblasts in response to TGFb and bleomycin is regulated by mTOR at the translational level. These findings indicate the importance of the Akt-mTOR signaling pathway in TGF-mediated fibrogenic events in vivo. J. Cell. Physiol. 226: 3004-3013, 2011. (C) 2011 Wiley-Liss, Inc.