Redirecting TGF-ß Signaling through the ß-Catenin/Foxo Complex Prevents Kidney Fibrosis.
J Am Soc Nephrol
; 29(2): 557-570, 2018 02.
Article
em En
| MEDLINE
| ID: mdl-29180394
ABSTRACT
TGF-ß is a key profibrotic factor, but targeting TGF-ß to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-ß signaling by preventing downstream profibrotic interaction of ß-catenin with T cell factor (TCF), thereby enhancing the interaction of ß-catenin with Foxo, a transcription factor that controls differentiation of TGF-ß induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-ß In iTregs derived from EL4 T cells treated with recombinant human TGF-ß1 (rhTGF-ß1) in vitro, inhibition of ß-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of ß-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of ß-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-ß1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-ß1 treatment alone. Coadministration of rhTGF-ß1 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-ß1. Together, our results show that diversion of ß-catenin from TCF- to Foxo-mediated transcription inhibits the ß-catenin/TCF-mediated profibrotic effects of TGF-ß while enhancing the ß-catenin/Foxo-mediated anti-inflammatory effects. Targeting ß-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Obstrução Ureteral
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Transdução de Sinais
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Linfócitos T Reguladores
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Beta Catenina
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Fatores de Transcrição TCF
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Fatores de Transcrição Forkhead
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Fator de Crescimento Transformador beta1
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Rim
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Am Soc Nephrol
Assunto da revista:
NEFROLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Austrália