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

Figure 4

Smad-dependent signaling pathways of TGF-β1 and BMP-7. The binding of TGF-β1 and BMP-7 to their primary receptors (receptors type II) allows the recruitment, transphosphorylation, and activation of the signaling receptors (receptors type I). The receptor type I of TGF-β1 phosphorylate Smad2 and Smad3. The receptor type I of BMP-7 phosphorylate Smad1, Smad5, and Smad8. These receptor-activated Smads form heterodimers with Smad4. The resulting Smad complexes are then translocated into the nucleus where they activate target genes involved either in the mesenchymal conversion of MCs (MMT) in the case of Smads2/3 or in the blocking/reversion of the mesenchymal transition (rMMT) in the case of Smads1/5/8. Smad6 and Smad7 control BMP-7- and TGF-β1-triggered Smad signaling by preventing the phosphorylation and/or nuclear translocation and by inducing receptor complex degradation through the recruitment of ubiquitin ligases. Extracellular regulation of TGF-β1 and BMP-7 is achieved by various molecules. CTGF inhibits BMP-7 and activates TGF-β1 signals by direct binding in the extracellular space. BMP-7 signaling might also be influenced by other BMP-7 modulators such as gremlin-1, kielin/chordin-like protein (KCP), or uterine sensitization-associated gene 1 (USAG-1).