Redirecting TGF- β Signaling through the β -Catenin/Foxo Complex Prevents Kidney Fibrosis

TGF- is a key profibrotic factor, but targeting TGF- to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF- signaling by preventing downstream profibrotic interaction of -catenin with T cell factor (TCF), thereby enhancing the interaction of -catenin with Foxo, a transcription factor that controls differentiation of TGF- induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF- In iTregs derived from EL4 T cells treated with recombinant human TGF- 1 (rhTGF- 1) , inhibition of -catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of -catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of -catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3 Ly5.1/5.2 mice revealed that coadministration of rhTGF- 1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF- 1 treatment alone. Coadministration of rhTGF- 1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF- 1. Together, our results show that diversion of -catenin from TCF- to Foxo-mediated transcription inhibits the -catenin/TCF-mediated profibrotic effects of TGF- while enhancing the -catenin/Foxo-mediated anti-inflammatory effects. Targeting -catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.