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Peer-reviewedCC BY-NC-NDInvestigative ophthalmology & visual science

Targeting Endoplasmic Reticulum Stress With Exogenous GDNF Promotes Diabetic Corneal Epithelial and Neural Repair via PI3K/AKT Signaling.

  • Haoyu Li1,2,3
  • Jianfeng Long2,4
  • Shirui Dai1,2
  • Wentao Han1,2,5
  • Liwei Zhang1,2,6
  • Baihua Chen1,2,7
7 affiliations
  1. 1Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.
  2. 2Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, People's Republic of China.
  3. 3https://orcid.org/0000-0002-9826-181X.
  4. 4Department of Clinical Nutrition, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.
  5. 5https://orcid.org/0000-0003-2650-0233.
  6. 6https://orcid.org/0000-0002-4349-5360.
  7. 7https://orcid.org/0000-0001-6367-9119.
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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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Cite

BibTeXRIS
BibTeX
@article{li2026targeting,
  title = {{Targeting Endoplasmic Reticulum Stress With Exogenous GDNF Promotes Diabetic Corneal Epithelial and Neural Repair via PI3K/AKT Signaling.}},
  author = {Haoyu Li and Jianfeng Long and Shirui Dai and Wentao Han and Liwei Zhang and Baihua Chen},
  journal = {Investigative ophthalmology \& visual science},
  year = {2026},
  month = oct,
  doi = {10.1167/iovs.67.12.24},
  url = {https://europepmc.org/article/MED/42872948},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Targeting Endoplasmic Reticulum Stress With Exogenous GDNF Promotes Diabetic Corneal Epithelial and Neural Repair via PI3K/AKT Signaling.
AU  - Haoyu Li
AU  - Jianfeng Long
AU  - Shirui Dai
AU  - Wentao Han
AU  - Liwei Zhang
AU  - Baihua Chen
PY  - 2026
DA  - 2026/10/01
JO  - Investigative ophthalmology & visual science
DO  - 10.1167/iovs.67.12.24
UR  - https://europepmc.org/article/MED/42872948
AB  - 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.
SN  - 0146-0404
SN  - 1552-5783
ER  -