Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. May 15, 2025; 16(5): 99473
Published online May 15, 2025. doi: 10.4239/wjd.v16.i5.99473
Effect of ranibizumab on diabetic retinopathy via the vascular endothelial growth factor/STAT3/glial fibrillary acidic protein pathway
Ye-Ting Lin, Jian Tan, Yu-Lin Tao, Wei-Wen Hu, Yi-Cang Wang, Jing Huang, Qiong Zhou, Ang Xiao
Ye-Ting Lin, Yu-Lin Tao, Wei-Wen Hu, Yi-Cang Wang, Jing Huang, Qiong Zhou, Ang Xiao, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
Jian Tan, Department of Ophthalmology, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang 330006, Jiangxi Province, China
Co-first authors: Ye-Ting Lin and Jian Tan.
Co-corresponding authors: Qiong Zhou and Ang Xiao.
Author contributions: Zhou Q and Xiao A conceived and designed the experiments; Lin YT and Tan J performed the experiments and wrote the paper; Hu WW, Wang YC, Tao YT, and Huang J analyzed and interpreted the data; All authors contributed to the article and approved the submitted version. Lin YT and Tan J contributed equally to this work as co-first authors based on three key reasons. First, both Lin YT and Tan J contributed equally to the research project, playing critical roles in its execution. Second, they were both actively involved in the subsequent manuscript revisions and communication processes, ensuring the quality and clarity of the paper. Lastly, assigning co-first authorship highlights the collaborative effort within our team and underscores the equal significance of their contributions. Therefore, we believe this designation is appropriate, as it reflects the teamwork, shared responsibility, and diversity embodied in our manuscript.
Supported by the Natural Science Foundation of Jiangxi Province, No. 20242BAB25489; National Natural Science Foundation of China, No. 82260211 and No. 81460092; Key Research and Development Project in Jiangxi Province, No. 20203BBG73058; and Chinese Medicine Science and Technology Project in Jiangxi Province, No. 2020A0166.
Institutional review board statement: The study was reviewed and approved by the Medical Research Ethics Committee of The First Affiliated Hospital of Nanchang University Institutional Review Board, Approval No. (2023) CDYFYYLK (01-047).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of Nanchang University, (IACUC protocol number: Protocol No. CDYFY-IACUC-202302QR049).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
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: Technical appendix, statistical code, and dataset available from the corresponding author at xiao2818161@126.com.
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: Ang Xiao, PhD, Doctor, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, No. 17 Yongwai Zheng Street, Donghu District, Nanchang 330006, Jiangxi Province, China. xiao2818161@126.com
Received: July 23, 2024
Revised: January 21, 2025
Accepted: March 13, 2025
Published online: May 15, 2025
Processing time: 275 Days and 18.4 Hours
Abstract
BACKGROUND

Diabetic retinopathy (DR) is the leading cause of vision loss in patients with diabetes. The vascular endothelial growth factor (VEGF) pathway plays a critical role in the pathogenesis of DR, and ranibizumab, an anti-VEGF agent, has shown promise in its treatment. Signal transducer and activator of transcription 3 (STAT3) is involved in inflammatory processes and cellular signaling, while glial fibrillary acidic protein (GFAP) is a marker of glial cell activation, both contributing to retinal damage in DR. However, the mechanisms by which ranibizumab affect early-stage DR through the VEGF/STAT3/GFAP pathway are not fully understood.

AIM

To investigate the role of ranibizumab in early DR via the VEGF/STAT3/GFAP pathway.

METHODS

Adult retinal pigment epithelial 19 (ARPE-19) cells and human retinal microvascular endothelial cells (HRMECs) were cultured under high-glucose conditions to simulate a diabetic environment. The effects of ranibizumab on cytokine mRNA and protein expression were analyzed by quantitative polymerase chain reaction and Western blot analysis. A diabetic rat model was induced with streptozotocin (60 mg/kg). Retinal changes, including retinal ganglion cell (RGC) apoptosis, vascular alterations, and cytokine expression, were evaluated using fundus fluorescein angiography, hematoxylin and eosin and periodic acid Schiff staining, immunofluorescence, confocal imaging, and Western blot analysis.

RESULTS

High-glucose conditions significantly increased the mRNA and protein levels of VEGF, STAT3, GFAP, and other cytokines in ARPE-19 and HRMECs. However, these levels were partially suppressed by ranibizumab. RGC apoptosis, vascular leakage, and elevated cytokine expression were observed during early-stage DR in diabetic rats. Ranibizumab treatment in diabetic rats reduced cytokine expression, restored RGCs, and repaired vascular networks.

CONCLUSION

Intravitreal ranibizumab modulates the VEGF/STAT3/GFAP pathway, suppresses cytokine expression, and promotes retinal repair, effectively delaying or preventing early DR progression.

Keywords: Diabetic retinopathy; Ranibizumab; Early stage; Vascular endothelial growth factor; Signal transducer and activator of transcription 3; Glial fibrillary acidic protein

Core Tip: Diabetic retinopathy (DR) is the leading cause of vision loss in patients with diabetes; however, the mechanisms behind its early stages remain unclear. This study explored the therapeutic effects of intravitreal ranibizumab on early DR through its effect on the vascular endothelial growth factor/STAT3/glial fibrillary acidic protein signaling pathway. Using high-glucose retinal cells and diabetic rat models, ranibizumab suppressed cytokine expression, reduced retinal ganglion cell apoptosis, and repaired vascular networks. These findings highlight the potential of ranibizumab in delaying or preventing early DR progression and provide a foundation for its clinical application.