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Updated: May 30, 2026
An Assay to Detect Protection of the Retinal Vasculature from Diabetes-Related Death in Mice
Published on: January 12, 2024
Notch signaling protects retina from nuclear factor-κB- and poly-ADP-ribose-polymerase-mediated apoptosis under
Xiuhong Qin1, Zhenzhen Zhang, Haitao Xu
1Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China.
Abstract:
Proliferative diabetic retinopathy, the primary cause of vision loss in adults, is one of serious microvascular complications caused by diabetes. Both poly-ADP-ribose-polymerase (PARP) and nuclear factor (NF)-κB signaling are involved in the injury process. Injury activates PARP, which in turn potentiates NF-κB activation and causes cell apoptosis. Like the NF-κB pathway, Notch1 signaling plays a key role in the regulation of cell proliferation, differentiation, and apoptosis. However, the connections between these signaling pathways are not well understood. In this study, we used both streptozotocin (STZ)-induced diabetic mice and human retinal vascular endothelial cells (HRVECs) cultured in high glucose to detect these relationships. We found that apoptosis was increased in both STZ-induced diabetic mice and high-glucose-treated HRVECs, which was due to increased activation of PARP, cleaved caspase3, and reduced expression of Notch1 and p-Akt. The results of Notch1 overexpression and knockdown indicated that Notch1 signaling participated in the interaction of PARP and p50, and inhibited PARP- and p50-mediated apoptosis directly. These phenomena could be blocked by pretreatment with the PI3K inhibitor wortmannin via reducing p-Akt levels. Thus, our study demonstrated that Notch1 signaling protects cells from PARP- and NF-κB-induced apoptosis under high glucose through the activation of Akt.
Insights
Diabetic retinopathy involves poly-ADP-ribose-polymerase (PARP) and nuclear factor-kappa B (NF-κB) signaling. This study shows Notch1 signaling protects against high glucose-induced apoptosis by activating Akt.
Area of Science:
- Ophthalmology
- Molecular Biology
- Endocrinology
Background:
- Proliferative diabetic retinopathy (PDR) is a leading cause of adult vision loss.
- Both poly-ADP-ribose-polymerase (PARP) and nuclear factor-kappa B (NF-κB) signaling pathways are implicated in diabetes-induced retinal injury.
- The interplay between PARP, NF-κB, and Notch1 signaling in PDR pathogenesis remains unclear.
Purpose of the Study:
- To investigate the relationship between PARP, NF-κB, and Notch1 signaling in the context of diabetic retinopathy.
- To elucidate the role of Notch1 in regulating apoptosis in high glucose conditions.
Main Methods:
- Utilized streptozotocin (STZ)-induced diabetic mice models.
- Employed human retinal vascular endothelial cells (HRVECs) cultured in high glucose.
- Performed Notch1 overexpression and knockdown experiments.
- Investigated the effect of PI3K inhibitor wortmannin.
Main Results:
- Increased apoptosis, PARP activation, and cleaved caspase-3 were observed in diabetic mice and high-glucose-treated HRVECs.
- Notch1 expression and Akt phosphorylation (p-Akt) were reduced under high glucose conditions.
- Notch1 overexpression inhibited PARP- and NF-κB (p50)-mediated apoptosis, while knockdown exacerbated it.
- Wortmannin treatment blocked these effects by reducing p-Akt levels.
Conclusions:
- Notch1 signaling plays a protective role against apoptosis induced by high glucose and PARP/NF-κB activation.
- The protective mechanism involves the activation of Akt.
- Targeting Notch1 and Akt pathways may offer therapeutic strategies for proliferative diabetic retinopathy.
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