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PEDF protects retinal pigment epithelium from ferroptosis and ameliorates dry AMD-like pathology in a murine model

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Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible vision damage among elderly individuals. There is still no efficient treatment for dry AMD. Retinal pigment epithelial (RPE) degeneration has been confirmed to play an important role in dry AMD. Recent studies have reported that ferroptosis caused by iron overload and lipid peroxidation may be the primary causes of RPE degeneration. However, the upstream regulatory molecules of RPE ferroptosis remain largely unknown. Pigment epithelium-derived factor (PEDF) is an important endogenic protective factor for the RPE. Our results showed that in the murine dry AMD model induced by sodium iodate (SI), PEDF expression was downregulated. Moreover, dry AMD-like pathology was observed in PEDF-knockout mice. Therefore, the aim of this study was to reveal the effects and mechanism of PEDF on RPE ferroptosis and investigate potential therapeutic targets for dry AMD. The results of lipid peroxidation and transmission electron microscope showed that retinal ferroptosis was significantly activated in SI-treated mice and PEDF-knockout mice. Restoration of PEDF expression ameliorated SI-induced retinal dysfunction in mice, as assessed by electroretinography and optical coherence tomography. Mechanistically, western blotting and immunofluorescence analysis demonstrated that the overexpression of PEDF could upregulate the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain-1 (FTH1), which proved to inhibit lipid peroxidation and RPE ferroptosis induced by SI. This study revealed the novel role of PEDF in ferroptosis inhibition and indicated that PEDF might be a potential therapeutic target for dry AMD.

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Data Availability

The experimental data reported in this study will be made available upon reasonable request from the corresponding author (laikunbei888@mail.sysu.edu.cn).

Abbreviations

AMD :

Age-related macular degeneration

RPE :

Retinal pigment epithelium

SI :

Sodium iodate

PEDF :

Pigment epithelial-derived factor

FTH1 :

Ferritin heavy chain 1

GPX4 :

glutathione peroxidase 4

ERG :

Electroretinography

H&E :

Hematoxylin and eosin

OCT :

Optical coherence tomography

qRT-PCR :

Quantitative real-time PCR

TEM :

Transmission electron microscope

ROS :

Reactive oxygen species

IF :

Immunofluorescence

CCK-8 :

Cell Counting Kit-8

FBS :

Fetal bovine serum

ZO-1 :

Zonula occludens protein 1

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Funding

This work was supported by National Natural Science Foundation of China (82171066). This article was also supported by Natural Science Foundation of Guangdong Province (2414050005730), so we added this funding in this version. Guangzhou Science and Technology Plan Project (202102010333 and SL2024A03J00359), and Guangdong Basic and Applied Basic Research Fund Project (2021A1515010895 and SL2023A04J00138).

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Author notes

  1. Wei Xiang and Longhui Li contributed equally to this study

Authors and Affiliations

  1. Department of Clinical Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Wei Xiang

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China

    Longhui Li, Qin Zhao, Zitong Chen & Kunbei Lai

  3. Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

    Yongcheng Zeng, Jinhui Shi & Guoquan Gao

Authors
  1. Wei Xiang
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  2. Longhui Li
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  3. Qin Zhao
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  4. Yongcheng Zeng
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  7. Guoquan Gao
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  8. Kunbei Lai
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Contributions

KBL, LHL and WX conceived the study and designed the experiments. WX and LHL performed the experiments, finalized the data set, and drafted the manuscript. WX and LHL contributed equally in this study. QZ participated in the experiments, preparation the resources and revised the original draft. YCZ, JHS, and ZTC contributed to the in vivo experiments. GQG, and KBL participated in the discussion. KBL supervised the entire study and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guoquan Gao or Kunbei Lai.

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Xiang, W., Li, L., Zhao, Q. et al. PEDF protects retinal pigment epithelium from ferroptosis and ameliorates dry AMD-like pathology in a murine model. GeroScience 46, 2697–2714 (2024). https://doi.org/10.1007/s11357-023-01038-3

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  • DOI: https://doi.org/10.1007/s11357-023-01038-3

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