Electroacupuncture ameliorates bladder dysfunction and fibrosis in diabetic rats: Underlying role of transient receptor potential vanilloid 1 in the dorsal root ganglion

Abstract

Objective: To assess the therapeutic effects of electroacupuncture (EA) in a rat model of diabetic cystopathy (DCP) and examine its impact on the expression of transient receptor potential vanilloid 1 (TRPV1) in the dorsal root ganglion (DRG).

Methods: Sixty male Sprague-Dawley rats were divided into four groups: control, DCP, EA, and sham EA (n = 10). DCP was induced using a high-fat diet, followed by streptozotocin injection. EA was administered at the Pangguangshu (BL 28) and Sanyinjiao (SP 6) acupoints for 8 weeks. Bladder function, structure, and molecular changes were evaluated using ultrasonography, urodynamic tests, bladder weight measurements, histological stainings (hematoxylin and eosin and Masson's trichrome stainings), transmission electron microscopy, immunohistochemical analysis, and Western blot for TRPV1 expression in the DRG.

Results: The DCP group exhibited significantly increased bladder weight, wall thickness, collagen fiber expression, maximum bladder capacity (MBC), post-void residual (PVR), and leakage point pressure, along with reduced bladder compliance (BC) and voiding efficiency (V%) compared with the control group (all P < .05). EA treatment significantly decreased bladder weight ( P = .003), collagen deposition (P = .002), wall thickness (P = .027), MBC (P = .046), and PVR (P = .023), and increased BC (P = .048) and V% (P = .022) compared with sham EA. Ultrastructural damage in DRG neurons was markedly ameliorated by EA. TRPV1 protein expression in the DRG was significantly higher in the EA group than in the sham EA group (immunohistochemistry: P = .003; Western blot: P = .001).

Conclusion: EA alleviates bladder dysfunction and remodeling in DCP rats, an effect associated with upregulated TRPV1 expression in the DRG, reduced bladder fibrosis, and preserved neuronal ultrastructure. These findings suggest a potential role for TRPV1 signaling in mediating the therapeutic effects of EA, warranting further functional investigation.

Keywords

Electroacupuncture / Diabetic cystopathy / Transient receptor potential vanilloid 1 / Dorsal root ganglion / Bladder remodeling

Funding

This study is supported by the National Natural Science Foundation of China (82405178), Qinchuangyuan Traditional Chinese Medicine Industry Innovation Cluster Project (L2024-QCY-ZYYJJQ-X163), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0509400) and Shaanxi Provincial Administration of Traditional Chinese Medicine Scientific Research Project (SZY-KJCYC-2025-JC-016).

CRediT authorship contribution statement

Xuke Han: Data curation, funding acquisition, and writing – original draft. Zifeng Chen: Methodology, investigation, and validation. Jianyue Ou: Methodology, investigation, and validation. Lue Ha: Methodology, investigation, and validation. Yifeng Shen: Methodology, investigation, and validation. Dongqi Zhou: Methodology, investigation, and validation. Chan Zhu: Formal analysis, and software. Luling Wang: Resources. Yuan Chen: Funding acquisition, and writing – review & editing. Qiu Chen: Project administration, supervision, and funding acquisition.

Declaration of competing interest

The authors declare that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Adegbehingbe OO, Ayoola O, Soyoye D, Adegbehingbe A . Urinary bladder wall thickness in type 2 diabetes mellitus patients. J Ultrason. 2022; 22(88): e12-e20.

[2] Blair Y, Wessells H, Pop—Busui R, Ang L, Sarma AV . Urologic complications in diabetes. J Diabet Complicat. 2022; 36(10): 108288.

[3] Confederat LG, Condurache MI, Alexa RE, Dragostin OM . Particularities of urinary tract infections in diabetic patients: a concise review. Medicina. 2023; 59(10): 1747.

[4] Nazarko L . Diabetic bladder dysfunction. Br J Community Nurs. 2024; 29(5): 232-237.

[5] Fernández—Ballester G, Fernández—Carvajal A, Ferrer—Montiel A . Progress in the structural basis of thermoTRP channel polymodal gating. Int J Mol Sci. 2023; 24(1): 743.

[6] Panchal SK, Bliss E, Brown L . Capsaicin in metabolic syndrome. Nutrients. 2018; 10(5): 630.

[7] Randhawa PK, Jaggi AS . TRPV(1) channels in cardiovascular system: a double edged sword. Int J Cardiol. 2017; 228: 103-113.

[8] Frias B, Merighi A . Capsaicin, nociception and pain. Molecules. 2016; 21(6): 797.

[9] Dai Y, Ye Q, Sun YM, et al. Acupuncture for diabetic neurogenic bladder: a protocol for systematic review and meta—analysis. Medicine (Baltim). 2021; 100: e24573.

[10] He YJ, Lin R, Qin NJ, et al. Manual acupuncture alleviates bladder dysfunction and ameliorates oxidative stress in a rat model of diabetic neurogenic bladder. Acupunct Med. 2025; 43: 344-353.

[11] Nori SL, Rocco ML, Florenzano F, et al. Increased nerve growth factor signaling in sensory neurons of early diabetic rats is corrected by electroacupuncture. Evid Based Complement Alternat Med. 2013; 2013: 652735.

[12] Li Y, Yin C, Li X, et al. Electroacupuncture alleviates paclitaxel—induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. Int J Mol Sci. 2019; 20(23): 5917.

[13] Li S, Zheng Y, Kang Y, et al. Electroacupuncture alleviates streptozotocin—induced diabetic neuropathic pain via suppressing phosphorylated CaMKIIα in rats. Neuroreport. 2024; 35(4): 258-268.

[14] Tykocki NR, Heppner TJ, Erickson CS, et al. Development of stress—induced bladder insufficiency requires functional TRPV1 channels. Am J Physiol Ren Physiol. 2018; 315(6): 1583-1591.

[15] He J, Yang J, Chen L, et al. Serum/glucocorticoid—regulated kinase 1—targeted transient receptor potential oxalate subtype 1 regulates bladder smooth muscle cell proliferation due to bladder outlet obstruction in mice via activated T cell nuclear factor transcription factor 2. IUBMB Life. 2022; 74(5): 463-473.

[16] Kwon J, Lee EJ, Cho HJ, et al. Antifibrosis treatment by inhibition of VEGF, FGF, and PDGF receptors improves bladder wall remodeling and detrusor overactivity in association with modulation of C—fiber afferent activity in mice with spinal cord injury. Neurourol Urodyn. 2021; 40(6): 1460-1469.

[17] Zhang Y, Zhang J, Hong M, et al. Suo Quan Wan ameliorates bladder overactivity and regulates neurotransmission via regulating myosin Va protein expression. Phytomedicine. 2022; 104: 154265.

[18] Zhang Y, Zhang J, Liu J, et al. Imbalance of bladder neurohomeostasis by myosin 5a aggravates diabetic cystopathy. Mol Med. 2025; 31(1): 91.

[19] Han X, Chen Y, Ha L, et al. Effects of electroacupuncture on bladder dysfunction and the expression of PACAP38 in a diabetic rat model. Front Physiol. 2022; 13: 1008269.

[20] Yang K, Wang Q . 50 week ultrasound imaging and ultrastructural abnormalities of bladder after sugar diuresis and diabetes mellitus in rats. Int Urol Nephrol. 2021; 53(10): 1995-2005.

[21] Abdelkhalek AS, Ali Youssef H, Saleh AS, Bollen P, Zvara P . Anesthetic protocols for urodynamic studies of the lower urinary tract in small rodents—a systematic review. PLoS One. 2021; 16(6): e0253192.

[22] Xu SF, Du GH, Abulikim K, Cao P, Tan HB . Verification and defined dosage of sodium pentobarbital for a urodynamic study in the possibility of survival experiments in female rat. BioMed Res Int. 2020; 2020: 6109497.

[23] Xue B, Kadeerhan G, Sun LB, et al. Circulating exosomal miR—16—5p and let—7e—5p are associated with bladder fibrosis of diabetic cystopathy. Sci Rep. 2024; 14(1): 837.

[24] Peyronnet B, Richard C, Bendavid C, et al. Urinary TIMP—2 and MMP—2 are significantly associated with poor bladder compliance in adult patients with spin. Bifida. Neurourol Urodyn. 2019; 38(8): 2151-2158.

[25] Wen Y, Wu J, Pu Q, et al. ABT—263 exerts a protective effect on upper urinary tract damage by alleviating neurogenic bladder fibrosis. Ren Fail. 2023; 45(1): 2194440.

[26] Metcalfe PD, Wang J, Jiao H, et al. Bladder outlet obstruction: progression from inflammation to fibrosis. BJU Int. 2010; 106(11): 1686-1694.

[27] Liu Q, Wang R, Ma N, Wang C, Chen W . Telmisartan inhibits bladder smooth muscle fibrosis in neurogenic bladder rats. Exp Ther Med. 2022; 23(3): 216.

[28] Brito R, Sheth S, Mukherjea D, Rybak LP, Ramkumar V . TRPV1: a potential drug target for treating various diseases. Cells. 2014; 3(2): 517-545.

[29] Andersson KE . Agents in early development for treatment of bladder dysfunction—promise of drugs acting at TRP channels. Expet Opin Invest Drugs. 2019; 28(9): 749-755.

[30] Bao Z, Dai X, Wang P, Tao Y, Chai D . Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1—dependent and—independent pathways. Cell Cycle. 2019; 18(12): 1379-1392.

[31] Philyppov IB, Paduraru ON, Andreev YA, Grishin EV, Shuba YM . Modulation of TRPV1—dependent contractility of normal and diabetic bladder smooth muscle by analgesic toxins from se. Anemone heteractis crispa. Life Sci. 2012; 91(19/20): 912-920.

[32] Jiang Z, Luo W, Liu L, Long Z . Enhancement sensitivity of TRPV1 in dorsal root ganglia via the SP—NK—1 pathway contributes to increased bladder organ sensitivity caused by prostatitis. Front Neurosci. 2024; 18: 1484980.

[33] Ramsay S, Keightley L, Brookes S, Zagorodnyuk V . TRPV1 and TRPM8 antagonists reduce cystitis—induced bladder hypersensitivity via inhibition of different sensitised classes of bladder afferents in Guinea pigs. Br J Pharmacol. 2023; 180(11): 1482-1499.

[34] Xue J, Liu Y, Zhang S, et al. Caffeine improves bladder function in diabetic rats via a neuroprotective effect. Exp Ther Med. 2021; 21(5): 501.

[35] Sasaki K, Chancellor MB, Phelan MW, et al. Diabetic cystopathy correlates with a long—term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia. J Urol. 2002; 168(3): 1259-1264.

[36] Facer P, Casula MA, Smith GD, et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol. 2007; 7: 11.

[37] Sidwell AB, Girard BM, Campbell SE, Vizzard MA . TRPV1 and mast cell involvement in repeated variate stress—induced urinary bladder dysfunction in adult female mice. Am J Physiol Ren Physiol. 2024; 327(3): 476-488.

[38] Sharopov BR, Gulak KL, Philyppov IB, Sotkis AV, Shuba YM . TRPV1 alterations in urinary bladder dysfunction in a rat model of STZ—induced diabetes. Life Sci. 2018; 193: 207-213.

[39] Hong S, Wiley JW . Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem. 2005; 280(1): 618-627.

[40] Zhang S, Tang L, Xu F, et al. TRPV1 receptor—mediated hypoglycemic mechanism of capsaicin in streptozotocin—induced diabetic rats. Front Nutr. 2021; 8: 750355.

[41] Mo X, Liu Q, Gao L, et al. The industrial solvent 1, 4—dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1. BMC Biol. 2022; 20(1): 10.