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Autophagy caused by oxidative stress promotes TGF-ß1-induced epithelial-to-mesenchymal transition in human peritoneal mesothelial cells.
Oh, Se-Hyun; Yook, Ju-Min; Jung, Hee-Yeon; Choi, Ji-Young; Cho, Jang-Hee; Park, Sun-Hee; Kim, Chan-Duck; Kim, Yong-Lim; Lim, Jeong-Hoon.
Afiliação
  • Oh SH; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Yook JM; Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea.
  • Jung HY; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Choi JY; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Cho JH; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Park SH; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Kim CD; Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea.
  • Kim YL; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • Lim JH; Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
Cell Death Dis ; 15(5): 365, 2024 May 28.
Article em En | MEDLINE | ID: mdl-38806451
ABSTRACT
Epithelial-to-mesenchymal transition (EMT) is one of the main causes of peritoneal fibrosis. However, the pathophysiological mechanisms of EMT, specifically its relationship with autophagy, are still unknown. This study aimed to evaluate the role of autophagy in transforming growth factor-beta 1 (TGF-ß1)-induced EMT in human peritoneal mesothelial cells (HPMCs). Primary cultured HPMCs were treated with TGF-ß1 (2 and 5 ng/mL) and changes in autophagy markers and the relationship between autophagy and EMT were evaluated. We also identified changes in EMT- and autophagy-related signaling pathways after autophagy and NADPH oxidase 4 (NOX4) inhibition. TGF-ß1 increased the generation of NOX4 and reactive oxygen species (ROS) in HPMCs, resulting in mitochondrial damage. Treatment with GKT137831 (20 µM), a NOX1/4 inhibitor, reduced ROS in the mitochondria of HPMC cells and reduced TGF-ß1-induced mitochondrial damage. Additionally, the indirect inhibition of autophagy by GKT137831 (20 µM) downregulated TGF-ß1-induced EMT, whereas direct inhibition of autophagy using 3-methyladenine (3-MA) (2 mM) or autophagy-related gene 5 (ATG5) gene silencing decreased the TGF-ß1-induced EMT in HPMCs. The suppressor of mothers against decapentaplegic 2/3 (Smad2/3), autophagy-related phosphoinositide 3-kinase (PI3K) class III, and protein kinase B (Akt) pathways, and mitogen-activated protein kinase (MAPK) signaling pathways, such as extracellular signal-regulated kinase (ERK) and P38, were involved in TGF-ß1-induced EMT. Autophagy and NOX4 inhibition suppressed the activation of these signaling pathways. Direct inhibition of autophagy and its indirect inhibition through the reduction of mitochondrial damage by upstream NOX4 inhibition reduced EMT in HPMCs. These results suggest that autophagy could serve as a therapeutic target for the prevention of peritoneal fibrosis in patients undergoing peritoneal dialysis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Autofagia / Transdução de Sinais / Espécies Reativas de Oxigênio / Estresse Oxidativo / Células Epiteliais / Fator de Crescimento Transformador beta1 / Transição Epitelial-Mesenquimal / NADPH Oxidase 4 Limite: Humans Idioma: En Revista: Cell Death Dis Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Autofagia / Transdução de Sinais / Espécies Reativas de Oxigênio / Estresse Oxidativo / Células Epiteliais / Fator de Crescimento Transformador beta1 / Transição Epitelial-Mesenquimal / NADPH Oxidase 4 Limite: Humans Idioma: En Revista: Cell Death Dis Ano de publicação: 2024 Tipo de documento: Article