1. Academic Validation
  2. SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1

SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1

  • World J Diabetes. 2025 Mar 15;16(3):101328. doi: 10.4239/wjd.v16.i3.101328.
Li-Fang Liang 1 Jia-Qi Zhao 1 Yi-Fei Wu 1 Hui-Jie Chen 1 Tian Huang 1 Xiao-He Lu 2
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China.
  • 2 Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China. luxh63@163.com.
Abstract

Background: Diabetic macular edema (DME) is the most common cause of vision loss in people with diabetes. Tight junction disruption of the retinal pigment epithelium (RPE) cells has been reported to induce DME development. SMAD-specific E3 ubiquitin protein Ligase (SMURF) 1 was associated with the tight junctions of cells. However, the mechanism of SMURF1 in the DME process remains unclear.

Aim: To investigate the role of SMURF1 in RPE cell tight junction during DME.

Methods: ARPE-19 cells treated with high glucose (HG) and desferrioxamine mesylate (DFX) for establishment of the DME cell model. DME mice models were constructed by streptozotocin induction. The trans-epithelial electrical resistance and permeability of RPE cells were analyzed. The expressions of tight junction-related and autophagy-related proteins were determined. The interaction between Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and SMURF1 mRNA was verified by RNA immunoprecipitation (RIP). SMURF1 N6-methyladenosine (m6A) level was detected by methylated RIP.

Results: SMURF1 and vascular endothelial growth factor (VEGF) were upregulated in DME. SMURF1 knockdown reduced HG/DFX-induced Autophagy, which protected RPE cell tight junctions and ameliorated retinal damage in DME mice. SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting Wnt inhibitory factor (WIF) 1 ubiquitination and degradation. IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.

Conclusion: M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation, which activated Autophagy to inhibit RPE cell tight junctions, ultimately promoting DME progression.

Keywords

Autophagy; Diabetic macular edema; N6-methyladenosine modification; Retinal pigment epithelium cells; SMAD specific E3 ubiquitin protein ligase 1; Vascular endothelial growth factor signaling pathway; WNT inhibitory factor 1.

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