Downregulated HDAC3 or up-regulated microRNA-296-5p alleviates diabetic retinopathy in a mouse model
Songtian Che1, Shuai Wu2, Peng Yu1
1Department of Ocular Fundus Disease, the Second Hospital of Jilin University, No. 4026, Yatai Street, Changchun 130041, Jilin, People's Republic of China.
Objective:
It has been demonstrated the efficacy of histone deacetylase 3 (HDAC3) in diabetes. Nevertheless, the function of HDAC3 in diabetic retinopathy (DR) remained largely obscure. Here, we investigated the HDAC3 effects in DR mice through the microRNA (miR)-296-5p/G protein subunit alpha i2 (GNAI2) axis.
Methods:
The mice diabetes model was established. HDAC3, GNAI2 and miR-296-5p levels in retina tissues of DR mice were evaluated. The weight, blood glucose, Evans blue leakage in DR mice, apoptosis of retinal ganglion cells, vascular endothelial growth factor (VEGF) and malondialdehyde (MDA) contents and superoxide dismutase (SOD) activity in DR mice were detected after miR-296-5p elevation or HDAC3 depletion. The relations among HDAC3, miR-296-5p and GNAI2 were validated.
Results:
HDAC3 and GNAI2 expressed at a high level while miR-296-5p expressed at a low level in retina tissues of DR mice. Restoring miR-296-5p or depleting HDAC3 reduced Evans blue leakage in DR mice, attenuated apoptosis of retinal ganglion cells, reduced VEGF and MDA, and enhanced SOD activity in serum and retinal tissues of DR mice. HDAC3 repressed miR-296-5p expression by binding to its promoter region, thereby enhancing GNAI2 expression.
Conclusion:
Depleting HDAC3 or restoring miR-296-5p suppresses apoptosis of retinal ganglion cells of DR mice via down-regulating GNAI2.
Insights
Histone deacetylase 3 (HDAC3) and G protein subunit alpha i2 (GNAI2) are upregulated in diabetic retinopathy (DR). Targeting HDAC3 or microRNA-296-5p (miR-296-5p) protects against DR by downregulating GNAI2.
Area of Science:
- Ophthalmology
- Molecular Biology
- Endocrinology
Background:
- Diabetic retinopathy (DR) is a significant complication of diabetes.
- The role of histone deacetylase 3 (HDAC3) in DR pathogenesis is not well understood.
- This study explores the involvement of HDAC3 in DR through the microRNA-296-5p (miR-296-5p)/G protein subunit alpha i2 (GNAI2) pathway.
Purpose of the Study:
- To investigate the effects of HDAC3 in a mouse model of diabetic retinopathy.
- To elucidate the relationship between HDAC3, miR-296-5p, and GNAI2 in the context of DR.
- To determine if modulating HDAC3 or miR-296-5p can ameliorate DR-related damage.
Main Methods:
- Established a mouse model of diabetes to study diabetic retinopathy.
- Quantified levels of HDAC3, GNAI2, and miR-296-5p in retinal tissues.
- Assessed retinal vascular leakage, ganglion cell apoptosis, and oxidative stress markers (VEGF, MDA, SOD) following interventions.
Main Results:
- HDAC3 and GNAI2 were significantly upregulated, while miR-296-5p was downregulated in the retinas of DR mice.
- Depletion of HDAC3 or restoration of miR-296-5p reduced vascular leakage, attenuated retinal ganglion cell apoptosis, and improved oxidative stress markers.
- HDAC3 was found to repress miR-296-5p expression, leading to increased GNAI2 levels.
Conclusions:
- HDAC3 and GNAI2 play a crucial role in the progression of diabetic retinopathy.
- Targeting HDAC3 or enhancing miR-296-5p expression offers a potential therapeutic strategy for DR.
- The findings highlight a novel regulatory axis (HDAC3/miR-296-5p/GNAI2) in diabetic retinopathy pathogenesis.
