Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2025; 16(8): 108101
Published online Aug 15, 2025. doi: 10.4239/wjd.v16.i8.108101
Hyperglycemia-induced overexpression of CREB3 L3 promotes the epithelial-to-mesenchymal transition in bladder urothelial cells in diabetes mellitus
Qing-Guo Wu, Ming-Jin Zhang, Yi-Bi Lan, Chun-Lei Ma, Wei-Jin Fu
Qing-Guo Wu, Department of Urology, Guigang City People Hospital, Guigang 530079, Guangxi Zhuang Autonomous Region, China
Ming-Jin Zhang, Yi-Bi Lan, Chun-Lei Ma, Wei-Jin Fu, Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
Co-first authors: Qing-Guo Wu and Ming-Jin Zhang.
Author contributions: Lan YB and Ma CL performed conceptualization, methodology, data curation, visualization, investigation, and writing of the original draft; Zhang MJ and Fu WJ were responsible for the project administration; Wu QG and Fu WJ were responsible for supervision, funding acquisition, resources, and review and editing of the manuscript. Wu QG and Zhang MJ contributed equally to this work.
Supported by Guangxi Natural Science Foundation, No. 2024GXNSFAA010031.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (2023-E046-01).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of the First Affiliated Hospital of Guangxi Medical University (2023-S753-01).
Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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 datasets used and/or analyzed during the current study are available from the corresponding author on 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: Wei-Jin Fu, Chief Physician, Department of Urology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Qinxiu District, Nanning 530022, Guangxi Zhuang Autonomous Region, China. fwjgxmu1978@163.com
Received: April 7, 2025
Revised: May 8, 2025
Accepted: July 2, 2025
Published online: August 15, 2025
Processing time: 131 Days and 20.1 Hours
Abstract
BACKGROUND

Diabetic cystopathy (DCP) is a complication affecting the lives of people with diabetes. However, the pathogenesis of DCP is not well known.

AIM

To investigate the potential mechanisms by which cAMP-responsive element-binding protein 3 like 3 (CREB3 L3) promotes the occurrence and development of DCP.

METHODS

High-throughput sequencing was used to analyze differentially expressed genes (DEGs) in bladder urothelium from patients with DCP and healthy controls. Gene enrichment analysis was conducted to assess the biological functions of DEG. Small interfering RNA technology was performed to silence the CREB3 L3 gene in both in vitro and in vivo experiments. Morphological changes in bladder urothelium from a DCP rat model were observed. Immunofluorescence and western blotting assay were performed to determine associated protein expression.

RESULTS

We identified significant DEGs through high-throughput sequencing. These genes were primarily enriched in inflammatory activation, epithelial-mesenchymal transition (EMT) and tight junction organization. Upregulated expression of both CREB3 L3 and C-reactive protein (CRP) in bladder urothelium from patients with DCP was accompanied by upregulated EMT markers including N-cadherin and vimentin proteins, but downregulated E-cadherin. Silencing CREB3 L3 attenuated the protein expression of CRP and EMT in SV-HUC-1 urothelial cells under hyperglycemic conditions and in the diabetes mellitus rat model at 4, 8, and 12 weeks. CREB3 L3 knockdown also reversed downregulation of the tight junction proteins occludin and claudin 1.

CONCLUSION

Hyperglycemia induces the upregulation of CREB3 L3 expression, thereby promoting the EMT and impairing tight junctions in bladder urothelial cells. Targeting CREB3 L3 in bladder urothelial cells is likely to be a key approach in preventing and treating DCP.

Keywords: Diabetic cystopathy; Epithelial-mesenchymal transition; Hyperglycemia

Core Tip: Diabetic cystopathy (DCP), a debilitating complication of diabetes mellitus, involves hyperglycemia-driven bladder dysfunction. This study identified cAMP-responsive element-binding protein 3 like 3 (CREB3 L3) as a novel mediator of DCP pathogenesis. Chronic hyperglycemia induced CREB3 L3 overexpression in bladder urothelium, promoting C-reactive protein-dependent inflammation, epithelial-mesenchymal transition (EMT), and tight junction disruption. Silencing CREB3 L3 in SV-HUC-1 urothelial cells and a DCP rat model reversed EMT markers (downregulation of N-cadherin downregulation and upregulation of E-cadherin), restored barrier proteins (occludin/claudin 1), and attenuated bladder remodeling. These findings establish CREB3 L3 as a therapeutic target to preserve urothelial integrity and mitigate DCP progression.