The HIF-1α/p53/miRNA-34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization.
J Cell Mol Med
; 25(3): 1700-1711, 2021 02.
Article
en En
| MEDLINE
| ID: mdl-33438362
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteína p53 Supresora de Tumor
/
Neovascularización Coroidal
/
MicroARNs
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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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