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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Role and mechanism of Roux-en-Y gastric bypass in the treatment of diabetic urinary bladder hyperactivity by reducing TRPV1 and P2X3
Guang-Yong Li, Shuai Ren, Bin-Cheng Huang, Jia-Jin Feng, Qiang-Qiang Wang, Qing-Jie Peng, Hai-Fu Tian, Le-Yi Yu, Cun-Ling Ma, Shu-Zhe Fan, Xiao-Jiang Chen, Mohammed Abdulkarem Al-Qaisi, Rui He
Guang-Yong Li, Shuai Ren, Bin-Cheng Huang, Jia-Jin Feng, Hai-Fu Tian, Mohammed Abdulkarem Al-Qaisi, Department of Urology, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
Guang-Yong Li, Peking University First Hospital Ningxia Women's and Children's Hospital, Yinchuan 750000, Ningxia Hui Autonomous Region, China
Qiang-Qiang Wang, Qing-Jie Peng, Le-Yi Yu, Cun-Ling Ma, Shu-Zhe Fan, Xiao-Jiang Chen, Rui He, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
Co-first authors: Guang-Yong Li and Shuai Ren.
Author contributions: Li GY and Ren S contributed equally to this work and should be considered co-first authors; Li GY was involved in acquisition of clinical data and drafting the manuscript; Yu LY, Ma CL, and Fan SZ contributed to drafting the manuscript; Tian HF, Feng JJ, Huang BC, Wang QQ, Peng QJ, and Chen XJ participated in animal experiments, data analysis, and manuscript revision; Al-Qaisi MA, Ren S, and He R revised the manuscript; All authors reviewed the manuscript before submission.
Supported by National Natural Science Foundation of China, No. 81860268 and No. 82201000; Ningxia Natural Science Foundation, No. 2021AAC02025; Ningxia Science and Technology Innovation Leading Talent Training Project; No. 2020GKLRLX06 and No. 2020GKLRLX11; Ningxia Medical University Research Project, No. XJKF240315; and Ningxia Key Research and Development Project, No. 2023BEG03021 and No. 2021BEB04034.
Institutional animal care and use committee statement: Ethical approval was obtained for the animal experiments conducted in the study (Certificate number: IACUC-NYLAC-2021-054).
Conflict-of-interest statement: No competing interests declared.
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 authors consent to data sharing.
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: Rui He, PhD, Full Professor, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, No. 1160 Shengli South Street, Xingqing District, Yinchuan 750000, Ningxia Hui Autonomous Region, China.
ruihe515@163.com
Received: April 28, 2024
Revised: October 1, 2024
Accepted: January 13, 2025
Published online: April 15, 2025
Processing time: 305 Days and 18.9 Hours
BACKGROUND
Diabetes mellitus (DM) is linked to an earlier onset and heightened severity of urinary complications, particularly bladder dysfunction, which profoundly impacts patient quality of life. Overactive bladder (OAB) is a common storage disorder of the lower urinary tract and is characterized by urgency, frequency, and nocturia. Several factors contribute to bladder dysfunction in diabetic individuals, including changes in urothelial signaling, detrusor morphology, and central nervous system regulation. The transient receptor potential vanilloid type 1 channel, expressed by bladder urothelial cells, is upregulated in OAB and plays a crucial role in ATP release during bladder filling. This ATP release subsequently activates purinergic receptor P2X3, further exacerbating OAB symptoms.
AIM
To clarify the mechanism of Roux-en-Y gastric bypass (RYGB) metabolic surgery to improve OAB in type 2 DM (T2DM).
METHODS
The model of T2DM was induced by feeding a high-fat diet to mice for 16 weeks. After 16 weeks, sham operation and RYGB operation were performed. The related indexes of glucose metabolism were also detected to evaluate the therapeutic effect, and the recovery degree of bladder function and micturition behavior of mice was assessed by urodynamics and micturition spot analysis.
RESULTS
Compared with the normal mice in the sham group, T2DM mice had increased urine spot count, uncontrolled urination behavior, shortened urination interval, and reduced bladder capacity. Immunohistochemistry and immunofluorescence costaining showed that Transient receptor potential vanilloid type 1 (TRPV1) and purinergic receptor P2X3 were both expressed in mouse bladder epithelial layer, and they had the same localization. In the bladder of T2DM mice, the mRNA and protein expression of TRPV1 and P2X3 were significantly increased. The ATP content in urine of T2DM mice was significantly higher than that of the sham group. After RYGB operation, the glucose metabolism index of the RYGB group was significantly improved compared with the OAB group. Comparing the results of urine spots, urodynamics, and histology, it was found that the function and morphological structure of the bladder in the RYGB group also recovered obviously. Compared with the OAB group, the expression of TRPV1 and P2X3 in the RYGB group was downregulated, and the level of inflammatory factors was significantly decreased. RYGB significantly decreased the content of ATP in urine and activated AMPK signaling.
CONCLUSION
RYGB downregulated the expression of TRPV1 by inhibiting inflammatory factors, thus inhibiting the enhancement of P2X3 by TRPV1. RYGB directly inhibited the activity of P2X3 by inhibiting ATP synthesis in the bladder epithelium to improve OAB.
Core Tip: Roux-en-Y gastric bypass as a metabolic surgery, effectively alleviates complications associated with diabetes. Although the mechanisms underlying diabetes-induced overactive bladder remain unclear, this study found that Roux-en-Y gastric bypass improved overactive bladder symptoms by suppressing inflammatory cytokines, reducing transient receptor potential vanilloid type 1 expression, and inhibiting ATP synthesis in bladder epithelial cells, ultimately leading to a direct inhibition of purinergic receptor P2X3 activity.
