{
  "abstract": "Background: Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Astrocyte senescence is highly prevalent in DR, but the underlying regulatory mechanism remains unclear. This study aims to investigate the role of the HIF-1α/PPAR-γ/SIRT1 axis in regulating retinal astrocyte senescence and endothelial function in DR. Methods: Mouse retinal astrocytes were exposed to high glucose (30 mM) to mimic diabetic conditions. Senescence was evaluated by β-galactosidase staining. Signaling pathways were manipulated using HIF-1α inhibitor (PX-478), PPAR-γ inhibitor (T0070907), SIRT1 agonist (SRT2104), and autophagy inhibitor (3-MA). Protein and mRNA levels of key factors were detected by Western blot and RT-qPCR. Astrocytes and retinal microvascular endothelial cells were co-cultured in Transwell systems to assess paracrine regulation on endothelial migration, proliferation, and apoptosis. Results: High glucose induced astrocyte senescence, inflammatory activation, and downregulation of GDNF and NRTN, accompanied by elevated HIF-1α and PPAR-γ, and reduced SIRT1 expression and autophagy activity. Inhibiting HIF-1α or activating SIRT1 attenuated senescence, apoptosis, and inflammation, restored autophagy, and upregulated GDNF/NRTN secretion. HIF-1α negatively regulated SIRT1 expression via PPAR-γ. Senescent astrocytes impaired endothelial function through reduced GDNF/NRTN; overexpression of GDNF or NRTN in astrocytes preserved endothelial migration and proliferation, and inhibited apoptosis. Conclusion: HIF-1α/PPAR-γ/SIRT1 axis mediates high glucose-induced astrocyte senescence via autophagy dysfunction. Senescent astrocytes disrupt retinal endothelial homeostasis by reducing GDNF/NRTN secretion. Targeting this axis may represent a novel neurovascular protective therapeutic strategy for DR.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Ophthalmology, Shandong Second Provincial General Hospital, Jinan, Shandong, P. R. China",
    "Department of Ophthalmology, Jinan Maternity and Child Care Hospital, Jinan, Shandong, P. R. China",
    "Nova Southeastern University College of Optometry, Davie, Florida, United States of America",
    "Jinan Second People Hospital, Jinan, Shandong, P. R. China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jing Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Shufen Fang"
    },
    {
      "affs": [
        2
      ],
      "name": "Ming Sun"
    },
    {
      "affs": [
        3
      ],
      "name": "Jue Wang"
    },
    {
      "name": "Yongqing Liu"
    },
    {
      "name": "Xuan Wang"
    },
    {
      "name": "Weiwei Liu"
    },
    {
      "name": "Lei Gao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3nke8fmfj64hd.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0362127",
  "fulltext_url": null,
  "id": "3nke8fmfj64hd",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0362127",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2731|Retinal Diseases and Treatments"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Endothelial cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Apoptosis"
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      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Autophagic cell death"
    ],
    [
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      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Epithelial cells/Endothelial cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Glial cells/Macroglial cells/Astrocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Organism development/Aging/Senescence"
    ],
    [
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      "/Biology and life sciences/Immunology/Immune response/Inflammation"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Physiological processes/Aging/Senescence"
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      "plos",
      "/Biology and life sciences/Physiology/Physiological processes/Secretion"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Endothelial cells"
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    [
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    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune response/Inflammation"
    ],
    [
      "plos",
      "/Research and analysis methods/Specimen preparation and treatment/Staining/Cell staining"
    ]
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  "openalex": "W7225380713",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/3nke8fmfj64hd.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:20:24Z",
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      "url": "https://doi.org/10.1371/journal.pone.0362127"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
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    {
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      "origin": "plos:immunology",
      "subfield": "immunology"
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      "origin": "plos:anatomy",
      "subfield": "physiology"
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  "title": "HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy",
  "title_text": "HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:20:48Z",
  "url": "https://research.draconitic.com/paper/3nke8fmfj64hd",
  "venue": "PLOS One",
  "versions": []
}