Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis
Por:
Urista, Juan, Maldonado, Mariel, Toscano-Marquez, Fernanda, Ramirez, Remedios, Balderas-Martínez Y.I., Becerril, Carina, Romero, Yair, Selman, Moises, Pardo, Annie
Publicada:
1 ene 2022
Categoría:
Biochemistry, genetics and molecular biology (miscellaneous)
Resumen:
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFß-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated ß Galactosidase activity, p53, p21, and the histone variant ?H2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence. © 2022 by the authors.
Filiaciones:
Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, 04510, Mexico
Instituto Nacional de Enfermedades Respiratorias, “Ismael Cosío Villegas”, Ciudad de Mexico, 14080, Mexico
Green Published, gold, All Open Access, Gold, Green
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