Mbd2 deficiency alleviates retinal cell apoptosisvia the miR-345-5p/Atf1 axis in high glucoseinjury and streptozotocin-induced diabetic mice

Yanni Ge; Ran Zhang; Yuqing Feng; Jinfang Lu; Huiling Li

doi:10.1016/j.omtn.2021.10.026

Mbd2 deficiency alleviates retinal cell apoptosisvia the miR-345-5p/Atf1 axis in high glucoseinjury and streptozotocin-induced diabetic mice

Mol Ther Nucleic Acids. 2021 Nov 3:26:1201-1214. doi: 10.1016/j.omtn.2021.10.026. eCollection 2021 Dec 3.

Authors

Yanni Ge^{1

2}, Ran Zhang^{1

2}, Yuqing Feng^{1

2}, Jinfang Lu^{1

2}, Huiling Li^{1

2}

Affiliations

¹ Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
² Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China.

Abstract

DNA methylation is considered to play an important role in the development of diabetic retinopathy. Here, our goal was to investigate the precise role of methyl-CpG binding domain protein 2 (Mbd2) in the apoptosis of retinal ganglion cells (RGCs) in the early diabetic retina. Mbd2 was significantly upregulated after high glucose (HG) treatment and played a proapoptotic role in RGCs during HG-induced apoptosis. Combining ChIP and gene microarray datasets, the results showed that Mbd2 possessed potential binding sites for miR-345-5p, thereby elevating the expression levels of miR-345-5p via the enhancement of promoter demethylation. Activating transcription factor 1 (Atf1) played an anti-apoptotic role during the process of apoptosis in RGCs and acted as the target gene for miR-345-5p. Furthermore, the number of surviving RGCs in the diabetic retina was increased in Mbd2-knockout mice when compared with wild-type mice and the visual function became better accordingly. Collectively, our data demonstrated that the HG-induced overexpression of Mbd2 in the retina was partly responsible for the apoptosis of retinal neuronal cells through the miR-345-5p/Atf1 axis. Therefore, the targeting of Mbd2 might represent a novel therapeutic strategy for the treatment of neurodegeneration in the early diabetic retina.

Keywords: Atf1; Mbd2; RGCs; apoptosis; diabetes; miR-345-5p.