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

Abstract

TGF-β is a key profibrotic factor, but targeting TGF-β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-β signaling by preventing downstream profibrotic interaction of β-catenin with T cell factor (TCF), thereby enhancing the interaction of β-catenin with Foxo, a transcription factor that controls differentiation of TGF-β induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-β In iTregs derived from EL4 T cells treated with recombinant human TGF-β1 (rhTGF-β1) in vitro, inhibition of β-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of β-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of β-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-β1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-β1 treatment alone. Coadministration of rhTGF-β1 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-β1. Together, our results show that diversion of β-catenin from TCF- to Foxo-mediated transcription inhibits the β-catenin/TCF-mediated profibrotic effects of TGF-β while enhancing the β-catenin/Foxo-mediated anti-inflammatory effects. Targeting β-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.

• Authors: Xi Qiao, Padmashree Rao, Yun Zhang, Lixin Liu, Min Pang, Hailong Wang, Min Hu, Xinrui Tian, Jianlin Zhang, Ye Zhao, Xin Maggie Wang, Chengshi Wang, Hong Yu, Fei Guo, Qi Cao, Yiping Wang, Yuan Min Wang, Geoff Yu Zhang, Vincent W Lee, Stephen I Alexander, Guoping Zheng, David C H Harris
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 2 Pg. 557-570 (02 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29180394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• CTNNB1 protein, mouse
• Cytokines
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Foxp3 protein, mouse
• ICG 001
• Pyrimidinones
• Recombinant Proteins
• Smad3 Protein
• Smad3 protein, mouse
• TCF Transcription Factors
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• beta Catenin

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line
• Cytokines (blood)
• Fibrosis
• Forkhead Box Protein O1 (metabolism)
• Forkhead Transcription Factors (genetics, metabolism)
• Inflammation (pathology)
• Kidney (pathology)
• Male
• Mice
• Promoter Regions, Genetic
• Protein Interaction Domains and Motifs
• Pyrimidinones (pharmacology)
• Recombinant Proteins (pharmacology)
• Signal Transduction
• Smad3 Protein (genetics)
• T-Lymphocytes, Regulatory (drug effects, metabolism, pathology)
• TCF Transcription Factors (metabolism)
• Transforming Growth Factor beta1 (metabolism, pharmacology)
• Ureteral Obstruction (pathology)
• beta Catenin (metabolism)