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.
Similar content being viewed by others
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
References
Fleckenstein M, Keenan TDL, Guymer RH, Chakravarthy U, Schmitz-Valckenberg S, Klaver CC, et al. Age-related macular degeneration. Nat Rev Dis Primers. 2021;7(1):31.
Blasiak J, Sobczuk P, Pawlowska E, Kaarniranta K. Interplay between aging and other factors of the pathogenesis of age-related macular degeneration. Ageing Res Rev. 2022;81:101735.
Sharma R, Bose D, Maminishkis A, Bharti K. Retinal pigment epithelium replacement therapy for age-related macular degeneration: are we there yet? Annu Rev Pharmacol Toxicol. 2020;60:553–72.
Tang Z, Ju Y, Dai X, Ni N, Liu Y, Zhang D, et al. HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration. Redox Biol. 2021;43:101971.
Sun Y, Zheng Y, Wang C, Liu Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis. 2018;9(7):753.
Gupta U, Ghosh S, Wallace CT, Shang P, Xin Y, Nair AP, et al. Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD. Autophagy. 2022;1–20.
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401–21.
Ouyang S, You J, Zhi C, Li P, Lin X, Tan X, et al. Ferroptosis: the potential value target in atherosclerosis. Cell Death Dis. 2021;12(8):782.
Zhao T, Guo X, Sun Y. Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging Dis. 2021;12(2):529–51.
Ma B, Zhou Y, Liu R, Zhang K, Yang T, Hu C, et al. Pigment epithelium-derived factor (PEDF) plays anti-inflammatory roles in the pathogenesis of dry eye disease. Ocul Surf. 2021;20:70–85.
Barnstable CJ, Tombran-Tink J. Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog Retin Eye Res. 2004;23(5):561–77.
Ding DC, Wen YT, Tsai RK. Pigment epithelium-derived factor from ARPE19 promotes proliferation and inhibits apoptosis of human umbilical mesenchymal stem cells in serum-free medium. Exp Mol Med. 2017;49(12):e411.
Carpino G, Cardinale V, Di Giamberardino A, Overi D, Donsante S, Colasanti T, et al. Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma. J Hepatol. 2021;75(6):1377–86.
He X, Cheng R, Park K, Benyajati S, Moiseyev G, Sun C, et al. Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway. Kidney Int. 2017;91(3):642–57.
Wang B, Wang L, Gu S, Yu Y, Huang H, Mo K, et al. D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration. Signal Transduct Target Ther. 2020;5(1):20.
Chan CM, Huang DY, Sekar P, Hsu SH, Lin WW. Reactive oxygen species-dependent mitochondrial dynamics and autophagy confer protective effects in retinal pigment epithelial cells against sodium iodate-induced cell death. J Biomed Sci. 2019;26(1):40.
Tang Z, Huo M, Ju Y, Dai X, Ni N, Liu Y, et al. Nanoprotection against retinal pigment epithelium degeneration via ferroptosis inhibition. Small Methods. 2021;5(12):e2100848.
Datta S, Cano M, Ebrahimi K, Wang L, Handa JT. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res. 2017;60:201–18.
Cai J, Nelson KC, Wu M, Sternberg P, Jones DP. Oxidative damage and protection of the RPE. Prog Retin Eye Res. 2000;19(2):205–21.
Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D’Amore PA, et al. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(1):110–20.
Eisenstein M. The quest to treat dry age-related macular degeneration. Nature. 2021;600(7887):S1.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.
Ru Q, Li Y, Xie W, Ding Y, Chen L, Xu G, et al. Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone Res. 2023;11(1):12.
Yang M, Tsui MG, Tsang JKW, Goit RK, Yao K-M, So K-F, et al. Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis. Cell Death Dis. 2022;13(5):468.
Becerra SP, Notario V. The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat Rev Cancer. 2013;13(4):258–71.
Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res. 2007;76(2):213–23.
Yamagishi S-I, Matsui T, Adachi H, Takeuchi M. Positive association of circulating levels of advanced glycation end products (AGEs) with pigment epithelium-derived factor (PEDF) in a general population. Pharmacol Res. 2010;61(2):103–7.
Xiang W, Li L, Hong F, Zeng Y, Zhang J, Xie J, et al. N-cadherin cleavage: a critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation. FASEB J. 2023;37(4):e22878.
Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci. 2003;4(8):628–36.
Comitato A, Subramanian P, Turchiano G, Montanari M, Becerra SP, Marigo V. Pigment epithelium-derived factor hinders photoreceptor cell death by reducing intracellular calcium in the degenerating retina. Cell Death Dis. 2018;9(5):560.
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).
Author information
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-023-01038-3