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Expression And Mechanism Of Action Of PIEZO1 In Bladder Dysfunction Caused By Pelvic Nerve Injury
Xingchen Liu, MD, PHD1, Zhaokai Zhou, PHD1, JIANGUO WEN, MD, PhD1, Wei JIa, MD, PhD2, Jinhua Hu, MD, PhD2, Guoxing Wu, MD, PhD3, Wei Lu, MD, PhD4.
1First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 2Guangzhou Women and Children's Medical Center, GuangZhou, China, 3Dongguan Children's Hospital, Dongguan, China, 4Xinyang Central Hospital, Xinyang, China.


BACKGROUND: Pelvic surgery may cause bilateral pelvic nerve injury (BPNI) that controls urination, resulting in weak contraction of the urethral muscles, increased residual urine and decreased bladder sensitivity, and even urinary retention that seriously affects the quality of life of patients. Therefore, it is necessary to continue to investigate the mechanism of bladder dysfunction after pelvic nerve injury and to find appropriate drug targets to prevent and alleviate this type of bladder dysfunction. METHODS: Female SD rats were selected and the bilateral pelvic nerves were squeezed to establish an animal model of BPNI bladder dysfunction, which was randomly divided into the BPNI-1W group, the BPNI-4W group and the sham-operated group (the Sham group). After 1 week of surgery in the BPNI-1W group, and 4 weeks after surgery in the BPNI-4W and the Sham groups, urodynamic examination was carried out to verify the establishment of the animal model, and the bladder tissues were collected, and transcriptome sequencing and screening of differentially expressed genes were carried out in the BPNI-1W and Sham groups to screen the signaling pathways involved. Bladder tissues of rats in the BPNI-1W and Sham groups were collected to transcriptome sequencing and screened for differentially expressed genes (DEGs), which were then subjected to GO and GSEA enrichment analyses to screen for the involved signalling pathways. Immunofluorescence and Western blot were used to detect changes and sites of expression of NLRP3, IL-1β, IL-18, gasdermin D and caspase1, key molecules of the PIEZO1 and NLRP3 signalling pathways in bladder tissues. RESULTS: Rats in the BPNI-1W group developed postoperative filling incontinence due to elevated bladder pressure, and the voiding function was partially restored in rats in the BPNI-4W group by decreasing bladder pressure. In enrichment analysis, DEGs were mainly enriched in inflammatory response, NLRP3, and cell proliferation-related signalling pathways. Western blot and immunofluorescence showed that NLRP3, IL-1β, IL-18, gasdermin D and caspase1, key molecules of the NLRP3 signalling pathway, were all highly expressed in the BPNI-1W group. In the BPNI-4W group, the expression of key molecules of NLRP3 signalling pathway decreased with the decrease of bladder pressure, and there was no significant difference with Sham group. The changes of PIEZO1 expression in bladder tissues of the three groups showed that PIEZO1 was highly expressed in the BPNI-1W group, and decreased in the BPNI-4W group with the partial recovery of bladder function. There was not significantly different between BPNI-4W group and Sham group. CONCLUSIONS: Increased bladder pressure after BPNI leads to an increase in PIEZO1 expression, which contributes to an increase in the release of inflammatory factors, such as IL-1β and IL-18, through the NLRP3 signalling pathway causing an inflammatory cascade response to damage neuronal cell. Inflammatory cascade response not only leads to further bladder denervation but also aggravates bladder fibrosis and promotes the progression of bladder dysfunction. The inflammatory response may be an important target for early intervention of bladder dysfunction after BPNI.


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