The farnesoid x receptor agonist edp-305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.
Carregando...
Data
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Federal de Minas Gerais
Descrição
Tipo
Artigo de periódico
Título alternativo
Primeiro orientador
Membros da banca
Resumo
Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance ofhepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established.Here, we investigate the effects of the FXR agonist EDP-305 in a mouse model of tubulointerstitial fibrosis viaunilateral ureteral obstruction (UUO). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 4,mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kgEDP-305. All animals were euthanized on postoperative d 12. EDP-305 dose-dependently decreased macrophageinfiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP-305 alsodose-dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen pro-portional area and kidney hydroxyproline levels. Finally, yes-associated protein (YAP) activation, a major driver offibrosis, increased after UUO injury and was diminished by EDP-305 treatment. Consistently, EDP-305 decreasedTGF-b1–induced YAP nuclear localization in human kidney 2 cells by increasing inhibitory YAP phosphorylation.YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP-305 could be used to treat renalfibrosis.—Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti,M., Caravan, P., Or, Y. S., Jiang, L.-J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP-305 reducesinterstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.
Abstract
Assunto
Rim, Insuficiência renal crônica, Fibrose renal
Palavras-chave
FXR, Kidney, Injury, UUO, YAP1
Citação
Departamento
Curso
Endereço externo
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201801699R