Retinal pigment epithelial (RPE) cells undergoing epithelial‑mesenchymal transition (EMT) are a key factor in promoting the progression of subretinal fibrosis. The klotho protein and gene exert anti‑fibrotic effects in multiple fibrotic diseases. However, the mechanisms involved in the role of klotho are unclear in subretinal fibrosis. The aim of the present study was to explore the effects of klotho on subretinal fibrosis induced by laser photocoagulation in mice and EMT induced by TGF‑β1 in RPE cells and the underlying molecular mechanisms. , klotho overexpression or knockdown was performed in ARPE‑19 cells (adult retinal Pigment Epithelial‑19), then TGF‑β1 treatment was applied. Using western blotting, expression of epithelial markers (zonula occludens‑1), mesenchymal signs (α‑smooth muscle actin, α‑SMA, N‑cadherin, N‑cad and collagen I), and the ERK1/2 and Wnt/β‑catenin signaling pathways were assessed. The proliferative ability of ARPE‑19 cells was examined by CCK‑8 and EdU test, and the migratory ability was examined by wound healing and Transwell assays. Furthermore, to explore the underlying molecular pathway of klotho overexpression, RNA‑sequencing (seq) was performed. , photocoagulation was used to induce subretinal fibrosis in mice, which occurs as a result of choroidal neovascularization (CNV), then recombinant mouse klotho protein was administered intravitreally. Upregulation of epithelial and downregulation of mesenchymal markers demonstrated that klotho overexpression prevented TGF‑β1‑induced EMT; klotho knockdown resulted in the opposite effects. Additionally, klotho overexpression suppressed cell proliferation and migration and attenuated ERK1/2 and Wnt/β‑catenin signaling activated by TGF‑β1. RNA‑seq results demonstrated that several signaling pathways, including cellular senescence and the TNF signaling pathway, were associated with anti‑fibrotic effects of klotho overexpression. , subretinal fibrotic areas were attenuated following klotho treatment in laser‑induced CNV lesions, as illustrated by immunofluorescence and Masson staining of the mouse eyes. Western blotting results that the protein levels of mesenchymal markers were significantly downregulated and those of epithelial markers were upregulated. In summary, the present study suggested that klotho may have therapeutic value in management of fibrotic vitreoretinal disorders such as subretinal fibrosis.
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http://dx.doi.org/10.3892/ijmm.2025.5486 | DOI Listing |
Int J Mol Med
March 2025
Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Retinal pigment epithelial (RPE) cells undergoing epithelial‑mesenchymal transition (EMT) are a key factor in promoting the progression of subretinal fibrosis. The klotho protein and gene exert anti‑fibrotic effects in multiple fibrotic diseases. However, the mechanisms involved in the role of klotho are unclear in subretinal fibrosis.
View Article and Find Full Text PDFAging Cell
January 2025
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Neovascular age-related macular degeneration (nAMD), characterized by choroidal neovascularization (CNV), is one of the leading causes of severe visual impairment and irreversible vision loss around the world. Subretinal fibrosis (SRF) contributes to the incomplete response to anti-vascular endothelial growth factor (VEGF) treatment and is one of the main reasons for long-term poor visual outcomes in nAMD. Reducing SRF is urgently needed in the anti-VEGF era.
View Article and Find Full Text PDFAdv Mater
December 2024
Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Ribonucleoprotein (RNP)-based CRISPR/Cas9 genome editing holds great potential for the treatment of choroidal neovascularization (CNV), which however, is challenged by the lack of efficient cytosolic protein delivery tools. Herein, reversibly-phosphorylated pro-proteins (P-proteins) with conjugated adenosine triphosphate (ATP) tags are engineered and coupled with a membrane-penetrating, guanidine-enriched, α-helical polypeptide (GP) to mediate robust and universal cytosolic delivery. GP forms salt-stable nanocomplexes (NCs) with P-proteins via electrostatic interaction and salt bridging, and the helix-assisted, strong membrane activities of GP enabled efficient cellular internalization and endolysosomal escape of NCs.
View Article and Find Full Text PDFGraefes Arch Clin Exp Ophthalmol
December 2024
Doheny Eye Institute, University of California, Los Angeles, 150 N. Orange Grove Blvd, Suite 232, Pasadena, CA, USA.
Anti-vascular endothelial growth factor (VEGF) therapies have transformed the treatment of retinal diseases. However, VEGF signaling is only one component of the complex, multifactorial pathophysiology of retinal diseases, and many patients have residual disease activity despite ongoing anti-VEGF treatment. The angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor receptor-2 (Ang/Tie2) signaling pathway is critical to endothelial cell homeostasis, survival, integrity, and vascular stability.
View Article and Find Full Text PDFExpert Opin Drug Saf
December 2024
Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Ophthalmology, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, China.
Background: Faricimab is a novel bispecific antibody drug for treating retinal disease. We aim to study the adverse events of faricimab based on the FDA Adverse Event Reporting System (FAERS) database.
Research Design And Methods: The FAERS data from 2020 to 2024 was extracted to conduct disproportionality analysis.
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