Blocking Mammalian Target of Rapamycin (mTOR) Attenuates HIF-1α Pathways Engaged-Vascular Endothelial Growth Factor (VEGF) in Diabetic Retinopathy
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Updated: Mar 9, 2026
Quantification of Vascular Parameters in Whole Mount Retinas of Mice with Non-Proliferative and Proliferative Retinopathies
Published on: March 12, 2022
Jie Wei1, Hua Jiang, Hongrui Gao
1Department of Ophthalmology, General Hospital of Jinan Military Command, Jinan, China.
Background/Aims:
Prior studies demonstrate that hypoxia inducible factor subtype 1α (HIF-1α) in retinal tissues is involved in development of diabetic retinopathy (DR). In this report, we particularly examined the role played by mammalian target of rapamycin (mTOR) in regulating expression of HIF-1α and its downstream pathway, namely vascular endothelial growth factor (VEGF).
Methods:
Streptozotocin (STZ) was systemically injected to induce hyperglycemia in rats. ELISA and Western Blot analysis were employed to determine the levels of HIF-1α and VEGF as well as expression of mTOR pathways in retinal tissues of control rats and STZ rats.
Results:
Our results show that HIF-1α and VEGF as well as VEGF receptor subtype 2 (VEGFR-2) were increased in STZ rats. Also, the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in diabetic retina compared with controls. Blocking mTOR by using rapamycin significantly attenuated activities of HIF-1α and VEGF signaling pathways.
Conclusion:
Our data for the first time revealed specific signaling pathways engaged in the development of DR, including the activation of mTOR and HIF-1α -VEGF mechanism. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of DR often observed in clinics.
Insights
The mammalian target of rapamycin (mTOR) pathway activates hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR). Targeting these pathways may offer new treatments for DR.
Area of Science:
- Ophthalmology
- Endocrinology
- Molecular Biology
Background:
- Diabetic retinopathy (DR) is a complication of diabetes.
- Hypoxia-inducible factor 1-alpha (HIF-1α) is implicated in DR development.
- The role of mammalian target of rapamycin (mTOR) in regulating HIF-1α and vascular endothelial growth factor (VEGF) in DR is not fully understood.
Purpose of the Study:
- To investigate the role of mTOR in regulating HIF-1α and VEGF expression in the context of diabetic retinopathy.
- To elucidate the specific signaling pathways involved in DR pathogenesis.
Main Methods:
- Hyperglycemia was induced in rats using streptozotocin (STZ).
- Enzyme-linked immunosorbent assay (ELISA) and Western Blot were used to quantify levels of HIF-1α, VEGF, and mTOR pathway components.
- Rapamycin was used to block mTOR activity.
Main Results:
- STZ-induced diabetic rats showed increased levels of HIF-1α, VEGF, and VEGF receptor 2 (VEGFR-2) in retinal tissues.
- Key components of the mTOR pathway, including p-mTOR, 4E-BP1, and S6K1, were upregulated in diabetic retinas.
- Rapamycin treatment significantly reduced the activity of HIF-1α and VEGF signaling pathways.
Conclusions:
- This study reveals the activation of the mTOR and HIF-1α-VEGF signaling pathways in DR development.
- These findings highlight potential therapeutic targets for managing diabetic retinopathy.
- Targeting mTOR, HIF-1α, or VEGF may offer novel treatment strategies for DR.
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