Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis

Figure 5

Non-Smad signaling in response to TGF-β1 and BMP-7. TGF-β1 activates MAP kinases JNK and p38 signaling and NF-κB through the activation of TAK1 by receptor-associated TRAF6. TGF-β1 also activates MAP kinase ERK 1/2 signaling through recruitment and phosphorylation of Shc by the TGF-β1 type I receptor. In MCs the p38-mediated pathway acts as modulator of the mesenchymal conversion by a feedback mechanism based on the downregulation of ERKs 1/2, NF-κB, and TAK-1 activities. Interestingly, BMP-7 activates p38 signaling by receptor-associated XIAB, which may contribute to the maintaining epithelial-like phenotype. TGF-β1 also induces PI3-K/Akt pathway leading to the activation of mTOR and the stabilization of β-catenin and snail through the inactivation of GSK-3β. As a result, β-catenin localizes to the nucleus, where it feeds into the Wnt signaling pathway by interacting with lymphoid enhancer factor-1/T-cell factor (LEF1/TCF) and contributes to the transcription of mesenchymal-related genes. In addition, the nuclear translocation of snail promotes the transcriptional repression of E-cadherin and other intercellular adhesion molecules.