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The HIF-1α/p53/miRNA-34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization.
Xie, Laiqing; Wang, Ying; Li, Quan; Ji, Xiaoyan; Tu, Yuanyuan; Du, Shu; Lou, Hui; Zeng, Xinwei; Zhu, Linling; Zhang, Ji; Zhu, Manhui.
Afiliación
  • Xie L; Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Wang Y; Department of Ophthalmology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
  • Li Q; Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, China.
  • Ji X; Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Tu Y; Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Du S; Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, China.
  • Lou H; Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, China.
  • Zeng X; Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Zhu L; Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Zhang J; Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, China.
  • Zhu M; Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
J Cell Mol Med ; 25(3): 1700-1711, 2021 02.
Article en En | MEDLINE | ID: mdl-33438362
Wet age-related macular degeneration (wAMD), characterized by choroidal neovascularization (CNV), is a leading cause of irreversible vision loss among elderly people in developed nations. Subretinal fibrosis, mediated by epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells, leads to unsuccessful anti-vascular endothelial growth factor (VEGF) agent treatments in CNV patients. Under hypoxic conditions, hypoxia-inducible factor-1α (HIF-1α) increases the stability and activation of p53, which activates microRNA-34a (miRNA-34a) transcription to promote fibrosis. Additionally, Klotho is a target gene of miRNA-34a that inhibits fibrosis. This study aimed to explore the role of the HIF-1α/p53/miRNA-34a/Klotho axis in subretinal fibrosis and CNV. Hypoxia-induced HIF-1α promoted p53 stability, phosphorylation and nuclear translocation in ARPE-19 cells (a human RPE cell line). HIF-1α-dependent p53 activation up-regulated miRNA-34a expression in ARPE-19 cells following hypoxia. Moreover, hypoxia-induced p53-dependent miRNA-34a inhibited the expression of Klotho in ARPE-19 cells. Additionally, the HIF-1α/p53/miRNA-34a/Klotho axis facilitated hypoxia-induced EMT in ARPE-19 cells. In vivo, blockade of the HIF-1α/p53/miRNA-34a/Klotho axis alleviated the formation of mouse laser-induced CNV and subretinal fibrosis. In short, the HIF-1α/p53/miRNA-34a/Klotho axis in RPE cells promoted subretinal fibrosis, thus aggravating the formation of CNV.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Neovascularización Coroidal / MicroARNs / Subunidad alfa del Factor 1 Inducible por Hipoxia / Epitelio Pigmentado de la Retina / Glucuronidasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Cell Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Neovascularización Coroidal / MicroARNs / Subunidad alfa del Factor 1 Inducible por Hipoxia / Epitelio Pigmentado de la Retina / Glucuronidasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Cell Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido