HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy
4 affiliations
- 1Department of Ophthalmology, Shandong Second Provincial General Hospital, Jinan, Shandong, P. R. China
- 2Department of Ophthalmology, Jinan Maternity and Child Care Hospital, Jinan, Shandong, P. R. China
- 3Nova Southeastern University College of Optometry, Davie, Florida, United States of America
- 4Jinan Second People Hospital, Jinan, Shandong, P. R. China
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.
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BibTeX
@article{wang2026hif1αpparγsirt1,
title = {{HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy}},
author = {Jing Wang and Shufen Fang and Ming Sun and Jue Wang and Yongqing Liu and Xuan Wang and Weiwei Liu and Lei Gao},
journal = {PLOS One},
year = {2026},
month = nov,
doi = {10.1371/journal.pone.0362127},
url = {https://doi.org/10.1371/journal.pone.0362127},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy
AU - Jing Wang
AU - Shufen Fang
AU - Ming Sun
AU - Jue Wang
AU - Yongqing Liu
AU - Xuan Wang
AU - Weiwei Liu
AU - Lei Gao
PY - 2026
DA - 2026/11/06
JO - PLOS One
DO - 10.1371/journal.pone.0362127
UR - https://doi.org/10.1371/journal.pone.0362127
AB - 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.
SN - 1932-6203
ER -