The HIF-1α/p53/miRNA-34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization.

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.

• Authors: Laiqing Xie, Ying Wang, Quan Li, Xiaoyan Ji, Yuanyuan Tu, Shu Du, Hui Lou, Xinwei Zeng, Linling Zhu, Ji Zhang, Manhui Zhu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 3 Pg. 1700-1711 (02 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33438362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• MIRN34 microRNA, human
• MicroRNAs
• Tumor Suppressor Protein p53
• Glucuronidase
• Klotho Proteins

Topics

• Animals
• Cell Line
• Choroidal Neovascularization (diagnostic imaging, etiology, metabolism, pathology)
• Disease Models, Animal
• Epithelial Cells (metabolism)
• Fibrosis
• Gene Expression Regulation
• Glucuronidase (metabolism)
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Klotho Proteins
• Mice
• MicroRNAs (genetics)
• Models, Biological
• Phosphorylation
• Protein Stability
• Protein Transport
• Retinal Pigment Epithelium (diagnostic imaging, metabolism, pathology)
• Signal Transduction
• Tumor Suppressor Protein p53 (metabolism)