Fibrosis is characterized by progressive excessive deposition of matrix components and may lead to organ failure. Transforming growth factor beta (TGF-β) is a key cytokine involved in tissue repair and fibrosis. TGF-β’s profibrotic signalling pathways converge at activation of β-catenin. β-catenin is an important transcription co-factor whose function depends on its binding partner. Our previous studies demonstrated that promoting β-catenin binding to Foxo via inhibition of its binding to TCF reduced kidney fibrosis in experimental murine models. Here, we investigated whether β-catenin/Foxo diverts TGF-β signalling from profibrotic to physiological epithelial healing. In an in vitro model of wound healing (scratch assay), and in an in vivo model of kidney injury, unilateral renal ischemia reperfusion (UIR), TGF-β treatment in combination with either ICG-001 or iCRT3 (β-catenin/TCF inhibitors) increased β-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, while reduced the TGF-β-induced mesenchymal differentialtion, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-β in C1.1 cells. Together, our results indicate that redirection of β-catenin binding from TCF to Foxo promotes β-catenin/Foxo-mediated epithelial repair. Targeting β-catenin/Foxo may rebuild normal structure of injured kidney.
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