Promotion of beta-Catenin/Forkhead Box Protein O Signaling Mediates Epithelial Repair in Kidney Injury

摘要

Fibrosis is characterized by progressively excessive deposition of matrix components and may lead to organ failure. Transforming growth factor-beta (TGF-beta) is a key cytokine involved in tissue repair and fibrosis. TGF-beta's profibrotic signaling pathways converge at activation of beta-catenin. beta-Catenin is an important transcription cofactor whose function depends on its binding partner. Promoting beta-catenin binding to forkhead box protein O (Foxo) via inhibition of its binding to T-cell factor (TCF) reduces kidney fibrosis in experimental murine models. Herein, we investigated whether beta-catenin/Foxo diverts TGF-beta signaling 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, TGF-beta treatment in combination with either ICG-001 or iCRT3 (beta-catenin/TCF inhibitors) increased beta-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, reduced the TGF-beta-induced mesenchymal differentiation, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-beta in C1.1 cells. Together, our results indicate that redirection of beta-catenin binding from TCF to Foxo promotes beta-catenin/Foxo-mediated epithelial repair. Targeting beta-catenin/Foxo may rebuild normal structure of injured kidney.