Liang LF, Zhao JQ, Wu YF, Chen HJ, Huang T, Lu XH. SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1. World J Diabetes 2025; 16(3): 101328 [DOI: 10.4239/wjd.v16.i3.101328]
Corresponding Author of This Article
Xiao-He Lu, Doctor, Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, No. 253 Gongye Avenue Central, Guangzhou 515282, Guangdong Province, China. luxh63@163.com
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Li-Fang Liang, Jia-Qi Zhao, Yi-Fei Wu, Hui-Jie Chen, Tian Huang, Xiao-He Lu, Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
Co-first authors: Li-Fang Liang and Jia-Qi Zhao.
Author contributions: Liang LF designed and managed the research and wrote the original manuscript; Zhao JQ provided the research methodology and guidance; Wu YF provided resources for this research; Chen HJ analyzed and managed the data and images; Huang T organized the data; Lu XH wrote the review, edited the manuscript and provided funding. Liang LF and Zhao JQ contributed equally to this work as co-first authors.
Supported by Natural Science Foundation of Guangdong Province, No. 2022A1515012346.
Institutional review board statement: The study was approved by the Ethics Committee of Zhujiang Hospital, Southern Medical University (No. 2024-KY-274-01) and all patients signed an informed consent form.
Institutional animal care and use committee statement: Animal study was approved by the Ethics Committee of Zhujiang Hospital, Southern Medical University (No. LAEC-2024-114).
Conflict-of-interest statement: The authors declare that there is no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Data sharing statement: The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-He Lu, Doctor, Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, No. 253 Gongye Avenue Central, Guangzhou 515282, Guangdong Province, China. luxh63@163.com
Received: September 11, 2024 Revised: December 6, 2024 Accepted: January 2, 2025 Published online: March 15, 2025 Processing time: 131 Days and 18.1 Hours
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.
Core Tip: In this study, we demonstrated that insulin like growth factor 2 mRNA binding protein 2 upregulates SMAD-specific E3 ubiquitin protein ligase (SMURF) 1 expression in an N6-methyladenosine-dependent manner, and subsequently SMURF1 activates the Wnt/β-catenin-vascular endothelial growth factor signaling pathway by promoting ubiquitination and degradation of WNT inhibitory factor 1 to promote autophagy, which ultimately disrupts the tight junctions of the retinal pigment epithelium cells and thus led to diabetic macular edema.
