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DNMT1-mediated PPARα methylation aggravates damage of retinal tissues in diabetic retinopathy mice
Ying Zhu1, Xinru Wang1, Xiaoyun Zhou2
1Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China.
Background:
Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear. Aim of this work was to investigate the mechanism of PPARα in DR.
Methods:
Human retinal capillary pericytes (HRCPs) were treated with high glucose (HG) to induce DR cell model. DR mouse model was established by streptozotocin injection, and then received 5-Aza-2-deoxycytidine (DAC; DNA methyltransferase inhibitor) treatment. Hematoxylin-eosin staining was performed to assess retinal tissue damage. PPARα methylation was examined by Methylation-Specific PCR. Flow cytometry and DCFH-DA fluorescent probe was used to estimate apoptosis and reactive oxygen species (ROS). The interaction between DNA methyltransferase-1 (DNMT1) and PPARα promoter was examined by Chromatin Immunoprecipitation. Quantitative real-time PCR and western blot were performed to assess gene and protein expression.
Results:
HG treatment enhanced the methylation levels of PPARα, and repressed PPARα expression in HRCPs. The levels of apoptotic cells and ROS were significantly increased in HRCPs in the presence of HG. Moreover, DNMT1 was highly expressed in HG-treated HRCPs, and DNMT1 interacted with PPARα promoter. PPARα overexpression suppressed apoptosis and ROS levels of HRCPs, which was rescued by DNMT1 up-regulation. In DR mice, DAC treatment inhibited PPARα methylation and reduced damage of retinal tissues.
Conclusion:
DNMT1-mediated PPARα methylation promotes apoptosis and ROS levels of HRCPs and aggravates damage of retinal tissues in DR mice. Thus, this study may highlight novel insights into DR pathogenesis.
Insights
DNA methyltransferase-1 (DNMT1) enhances PPARα methylation, increasing cell damage in diabetic retinopathy (DR). Inhibiting DNMT1 may offer a new therapeutic strategy for DR by reducing retinal tissue damage.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Diabetic retinopathy (DR) is a complication of diabetes with unclear mechanisms.
- Peroxisome proliferator-activated receptor alpha (PPARα) is implicated in DR pathogenesis.
Purpose of the Study:
- To investigate the mechanism of PPARα in diabetic retinopathy.
- To explore the role of DNA methyltransferase-1 (DNMT1) in regulating PPARα expression in DR.
Main Methods:
- Established high glucose (HG)-induced DR cell models using human retinal capillary pericytes (HRCPs).
- Utilized DR mouse models treated with 5-Aza-2-deoxycytidine (DAC).
- Assessed apoptosis, reactive oxygen species (ROS), gene/protein expression, and DNA methylation levels.
Main Results:
- HG treatment increased PPARα methylation and repressed PPARα expression in HRCPs, leading to elevated apoptosis and ROS.
- DNMT1 interacted with the PPARα promoter and its upregulation rescued PPARα overexpression effects.
- DAC treatment in DR mice reduced PPARα methylation and retinal tissue damage.
Conclusions:
- DNMT1-mediated PPARα methylation promotes apoptosis and ROS, exacerbating retinal damage in DR.
- This mechanism highlights DNMT1 as a potential therapeutic target for DR.
