ArticleInvestigative ophthalmology & visual science2026
Targeting Endoplasmic Reticulum Stress With Exogenous GDNF Promotes Diabetic Corneal Epithelial and Neural Repair via PI3K/AKT Signaling.
Article in Investigative ophthalmology & visual science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: This study investigates the therapeutic potential and the core signaling associated with glial cell line-derived neurotrophic factor (GDNF) in alleviating diabetic keratopathy (DK). Methods: In vitro, human corneal epithelial cells (HCECs) were subjected to glucolipotoxic stress to simulate the type 2 diabetes mellitus (T2DM) microenvironment, with or without GDNF and PI3K/AKT pathway modulators. In vivo, a T2DM mouse model was established using a combination of high-fat diet feeding and streptozotocin administration, and recombinant GDNF was administered subconjunctivally. Cellular functions were evaluated using standard assays. Protein expressions in HCECs, murine corneas, and trigeminal ganglia (TG) were quantified via Western blotting. Ultrastructural endoplasmic reticulum (ER) alterations were observed using transmission electron microscopy. Clinical evaluations, including fluorescein staining, mechanical sensitivity, and wound healing rates were systematically conducted alongside whole-mount corneal nerve immunolabeling. Results: GDNF intervention effectively restored the impaired proliferative and migratory capacities of HCECs, attenuated apoptosis, and alleviated ER stress induced by glucolipotoxicity. Notably, pharmacological inhibition of the PI3K/AKT pathway significantly abrogated these protective effects. In vivo, subconjunctival GDNF administration expedited epithelial restoration, stimulated subbasal nerve regrowth, and rescued sensitivity within the diabetic murine cornea. Furthermore, exogenous GDNF successfully mitigated ER stress and reactivated the suppressed PI3K/AKT signaling cascade in both the corneal epithelium and the corresponding TG. Conclusions: Exogenous GDNF significantly accelerates epithelial restoration while concurrently driving neural regeneration within the diabetic cornea. These dual protective effects are mechanistically driven by the reactivation of the PI3K/AKT signaling axis to mitigate ER stress.
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