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Amrisha Verma, Zhiying Shan, Bo Lei, Xuan Liu, Takahiko Nakagawa, Maria B. Grant, William W. Hauswirth, Xun Xu, Mohan K. Raizada, Qiuhong Li; Hyperglycemia Induced Methylation Changes In Genes Of Ocular Renin Angiotensin System. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5952.
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Hyperactivity of circulating and tissue renin angiotensin system (RAS) has been implicated in the pathogenesis of diabetic retinopathy. We have found that the ACE and AT1R genes are highly elevated earlier in diabetic retinas and this elevation is sustained during the progression of diabetic retinopathy. Since emerging evidence indicates that the methylation status of the promoter regions of the ACE and AT1R genes plays an important role in the regulation of the vasodeleterious axis of the RAS, we aimed to test the hypothesis that hypomethylation of the promoter regions of the ACE and AT1R genes is responsible for the sustained imbalance in the vasoprotective/vasodeleterious axis of the ocular RAS in the diabetic retina.
A detailed analysis of CpG island sequence in the upstream regions of mouse AT1R and ACE genes was conducted using web-based tool. Genomic DNA was isolated from retinas at 2 month after STZ-induced diabetes, as well as age-matched controls. The methylation status of these regions was examined by bisulfite-based genomic modification followed by combined bisulfite restriction analysis (COBRA) and direct sequencing to map the methylation sites.
Several clusters of CpG islands in the proximal promoter, the upstream of the transcriptional start sites, as well as the first exon, were found in the mouse ACE and AT1Ra genes. The COBRA clearly revealed reduced methylation in these regions in samples isolated from diabetic retina as compared to control retinas.
The promoter regions of ACE and AT1Ra genes are hypomethylated in the retina in response to the hyperglycemic condition. This hypomethylation of these genes may be responsible for the sustained elevation of their expression during the progression of diabetes, and may contribute to the development and progression of diabetic retinopathy.
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