4.5 Article

MiR-423-5p activated by E2F1 promotes neovascularization in diabetic retinopathy by targeting HIPK2

Journal

DIABETOLOGY & METABOLIC SYNDROME
Volume 13, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s13098-021-00769-7

Keywords

Angiogenesis; Diabetic retinopathy; E2F1; miR-423-5p; HIPK2; HIF1 alpha/VEGF signaling

Funding

  1. Natural Science Foundation of Zhejiang Province [LQ18H120002]
  2. Zhejiang Provincial Medical and Health Science and Technology Project [2020KY578,2020KY150]

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The study demonstrates that E2F1 activates miR-423-5p transcription to promote angiogenesis during DR by suppressing HIPK2 expression to disinhibit the HIF1 alpha/VEGF signaling pathway. These findings may offer potential therapeutic strategies for DR by targeting the E2F1/miR-423-5p/HIPK2 axis.
Background: Diabetic retinopathy (DR) is a diabetic complication and the primary cause of blindness in the world. However, the treatments of DR are challenging given its complicated pathogenesis. Here, we investigated the molecular mechanisms of DR by focusing on the function of E2F1/miR-423-5p/HIPK2/HIF1 alpha/VEGF axis. Methods: Cultured retinal endothelial cells (hRMECs, hRECs) were treated with 25 mM glucose to mimic the high glucose-induced DR in vitro. Streptozotocin (STZ) was injected into mice to induce DR in mice. qRT-PCR, western blotting, immunohistochemistry, and ELISA were employed to measure levels of E2F1, miR-423-5p, HIPK2, HIF1 alpha, and VEGF. H&E staining was utilized to examine retinal neovascularization. CCK-8 assay, transwell assay, and vascular tube formation assay were used to assess the cell viability, migration, and angiogenesis. Dual luciferase assay was performed to validate interactions between E2F1 and miR-423-5p, miR-423-5p and HIPK2. Results: HG treatment increased the cell viability, migration, and angiogenesis accompanied by upregulation of E2F1, miR-423-5p, HIF1 alpha, and VEGF levels, but reduction in HIPK2 expression. Knockdown of E2F1 or miR-423-5p suppressed the HG-induced increases in cell viability, migration, and angiogenesis. E2F1 transcriptionally activated miR-423-5p expression and miR-423-5p mimics blocked the effects of E2F1 knockdown on angiogenesis. Moreover, miR-423-5p directly targeted HIPK2 to disinhibit HIF1 alpha/VEGF signaling. Knockdown of HIPK2 reversed the effects of miR-423-5p inhibitor on cell viability, migration, and angiogenesis. Knockdown of E2F1 suppressed neovascularization during DR in vivo. Conclusions: E2F1 activates miR-423-5p transcription during DR to promote angiogenesis via suppressing HIPK2 expression to disinhibit HIF1 alpha/VEGF signaling. Strategies targeting E2F1/miR-423-5p/HIPK2 axis could be potentially used for DR treatment.

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