Abstract
BackgroundPeroxisome 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.MethodsHuman 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.ResultsHG 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.ConclusionDNMT1-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.
Highlights
Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear
There was no significant difference in the methylation and expression of PPARα between Normal glucose (NG) and Mannose groups (Fig. 1B, C)
QRT-PCR and western blot (WB) data revealed that high glucose (HG) treatment caused a down-regulation of PPARα in Human retinal capillary pericytes (HRCPs), which was partly rescued by DAC treatment (Fig. 1D, E)
Summary
Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear. The blood glucose levels of diabetic patients have a great influence on diabetic complications. If a diabetic patient with hyperglycemia for a long time, even if the levels of blood glucose are controlled in the later stage, diabetes-related complications are still prone to occur. This phenomenon is called “metabolic memory” [12,13,14]. The existence of “metabolic memory” has become a major obstacle to diabetic complication treatment, but its mechanism has not been fully elucidated. Epigenetics is expected to become an important breakthrough in revealing the phenomenon of “metabolic memory”, thereby providing new insights for diabetes complication treatment
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