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RBM15 promotes hyperglycemia-induced retinal endothelial cell injury by regulating FOXO3 stability via m6A
Yang Yu1, Yuqing Ren2, Su Dong3
1Department of Ophthalmology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, P.R. China. ykyyyy2018@163.com.
Abstract:
Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, is a leading cause of vision loss among working-age adults. Although N6-methyladenosine (m6A), a prevalent post-transcriptional mRNA modification, is emerging as a key regulator in DR, the specific role of the m6A writer RBM15 in hyperglycemia-induced retinal endothelial cell injury remains poorly defined. Here, we found that RBM15 is upregulated in the retinas of diabetic mice as well as in endothelial cells (ECs) challenged with high glucose (HG). Knockdown of RBM15 significantly mitigated HG-induced apoptosis and rescued autophagy deficiency in retinal ECs. In vivo, downregulation of RBM15 effectively attenuated retinal thinning, acellular capillary formation, and vascular leakage in diabetic mice. Mechanistically, we demonstrated that RBM15 regulates HG-induced apoptosis and autophagy deficiency in ECs by modulating FOXO3 mRNA stability in an m6A-dependent manner. In conclusion, our findings identify the RBM15/m6A/FOXO3 signaling pathway as a critical regulator of HG-induced retinal microvascular dysfunction and highlight RBM15 as a potential therapeutic target for the treatment of DR.
Insights
Researchers identified the RBM15/m6A/FOXO3 pathway as crucial in diabetic retinopathy (DR). Targeting RBM15 may offer a new treatment for DR by protecting retinal endothelial cells from high glucose damage.
Area of Science:
- Ophthalmology
- Molecular Biology
- Endocrinology
Background:
- Diabetic retinopathy (DR) is a major cause of vision loss.
- N6-methyladenosine (m6A) modifications are increasingly recognized as regulators in DR.
- The role of the m6A writer RBM15 in high glucose-induced retinal endothelial cell injury is unclear.
Purpose of the Study:
- To investigate the function of RBM15 in high glucose-induced retinal endothelial cell injury.
- To elucidate the molecular mechanism by which RBM15 affects diabetic retinopathy.
Main Methods:
- Examined RBM15 expression in diabetic mouse retinas and high glucose-challenged endothelial cells (ECs).
- Utilized RBM15 knockdown in vitro and in vivo models.
- Assessed apoptosis, autophagy, retinal thinning, capillary formation, and vascular leakage.
- Investigated the m6A-dependent modulation of FOXO3 mRNA stability.
Main Results:
- RBM15 was upregulated in diabetic retinas and high glucose-treated ECs.
- RBM15 knockdown reduced EC apoptosis and rescued autophagy deficiency.
- Downregulating RBM15 attenuated DR hallmarks in diabetic mice.
- RBM15 regulated EC apoptosis and autophagy via m6A-dependent control of FOXO3 mRNA stability.
Conclusions:
- The RBM15/m6A/FOXO3 pathway is a key regulator of high glucose-induced retinal microvascular dysfunction.
- RBM15 emerges as a potential therapeutic target for diabetic retinopathy.
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