Non-invasive voiding assessment in conscious mice

Sidler, Martin; Aitken, Karen; Forward, Sarah; Vitkin, I. Alex; Bägli, Darius

doi:10.14440/bladder.2018.582

Cited by 6 publications

(6 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11,33 However, inhibition of S6K as opposed to the entire mTOR pathway in mice during obstruction lead to worsening of bladder hypertrophy. 7 Herein, it was observed that BDNF induces extracellular signal-regulated kinase and S6K1 and is associated with loss of differentiation in BSMCs, consistent with previous studies. 10 In particular, high-dose sustained BDNF signaling may play a role in bladders by causing sustained extracellular signal-regulated kinase signaling, which is known to have differential effects on BSMC growth and neurons.…”

Section: Bdnf Signals To Proproliferative Pathways In Bladder Smooth supporting

confidence: 91%

DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF

Sidler

Aitken

Jiang

et al. 2018

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Chronic bladder obstruction and bladder smooth muscle cell (SMC) stretch provide fibrotic and mechanical environments that can lead to epigenetic change. Therefore, we examined the role of DNA methylation in bladder pathology and transcriptional control. Sprague-Dawley female rats underwent partial bladder obstruction by ligation of a silk suture around the proximal urethra next to a 0.9-mm steel rod. Sham operation comprised passing the suture around the urethra. After 2 weeks, rats were randomized to normal saline or DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (DAC) at 1 mg/kg, three times/week intraperitoneally. After 6 weeks, bladders were weighed and divided for histology and RNA analysis by high-throughput real-time quantitative PCR arrays. DAC treatment during obstruction in vivo profoundly augmented brain-derived neurotrophic factor (BDNF) expression compared with the obstruction with vehicle group, which was statistically correlated with pathophysiologic parameters. BDNF, cysteine rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF) expression clustered tightly together using Pearson's correlation analysis. Their promoters were associated with the TEA domain family member 1 (TEAD1) and Yes-associated protein 1/WW domain containing transcription regulator 1 pathways. Interestingly, DAC treatment increased BDNF expression in bladder SMCs (P < 0.0002). Stretch-induced BDNF was inhibited by the YAP/WWTR1 inhibitor verteporfin. Verteporfin improved the SMC phenotype (proliferative markers and SMC marker expression), in part by reducing BDNF. Expression of BDNF is limited by DNA methylation and associated with pathophysiologic changes during partial bladder outlet obstruction and SMC phenotypic change in vitro.

show abstract

Section: Bdnf Signals To Proproliferative Pathways In Bladder Smooth supporting

confidence: 91%

DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF

Sidler

Aitken

Jiang

et al. 2018

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although cell biology and molecular biology have developed rapidly [ 16 , 17 ], the use of animal models to observe the biological activities and overall status of the body is necessary [ 18 ]. Rodent models are important for studying bladder physiology and pathophysiology [ 19 ]. Currently, the most commonly used surgical procedure for establishing an overactive bladder model is the creation of a partial bladder outlet obstruction [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of an overactive bladder model in mice

Zhong

2023

BMC Urol

View full text Add to dashboard Cite

Background Overactive bladder (OAB) is a syndrome characterized by symptoms of urinary urgency, often accompanied by frequent urination and nocturia or urge incontinence. Methods Twenty female ICR mice were randomly divided into pBOO (partial bladder outlet obstruction) and control groups. The mouse OAB model was constructed by ligating the bladder outlet. Eight weeks after the operation, the methods of voiding spot on paper (VSOP), isolated detrusor muscle, and HE staining were used for analysis and research. Results After the operation, two mice in the experimental and one in control died, and one in the control groups had an abnormal bladder size, so it was excluded from the statistical analysis. Eight weeks after the operation, there was an insignificant difference (P = 0.15) in the body weight of mice in the pBOO (26.54 ± 2.62 g) and the control group (24.84 ± 1.76 g). The number of urinations in 12 h was significantly higher (P < 0.001) in the pBOO (7.63 ± 1.19) than in the control group (4.13 ± 0.99). Also, the 12-h urine volume of pBOO (1491.23 ± 94.72 μL) was significantly greater (P = 0.006) than that of the control group (1344.86 ± 88.17 μL). The isolated bladder of the pBOO mice was significantly heavier than that in the control group (53.16 ± 1.79 mg vs. 24.54 ± 1.80 mg, P < 0.001), the horizontal and vertical length of the bladder in pBOO group were larger than those in the control group (P < 0.001). The detrusor thickness of pBOO group (357.50 ± 11.88 µm) was significantly thicker than that of control group (258.52 ± 17.22 µm, P < 0.001), and the isolated muscle strip was more sensitive to carbachol stimulation. According to HE staining, the bladder wall of the pBOO mice was significantly thickened. Conclusions A pBOO-mediated mouse OAB model was successfully established by ligating the bladder outlet.

show abstract

“…There is high variability and high mortality in traditional obstruction as the bladder neck and ureters are minute and susceptible to damage during surgery. By measuring bladder function non-invasively in NeMO (15,16,28), we could determine the efficacy of treatments without a high baseline mortality rate or secondary effects of sham surgeries.…”

Section: Discussionmentioning

confidence: 99%

Human - murine concordance of molecular signatures in nerve-sparing murine partial bladder outlet obstruction (NeMO)

Sidler

Ahmed

Jiang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Recently we demonstrated the utility of a nerve-sparing mid-urethra model of partial outlet obstruction (NeMO) that has high consistency and minimal mortalities, unlike the traditional model proximal to the bladder neck. Our goal was to uncover potential therapeutic targets by investigating the genome wide transcriptional changes and pathways altered in NeMO to compare with published human bladder obstruction data. We performed RNAseq and analysed the differentially upregulated and downregulated genes for associated pathways, transcription factor binding site analysis (TFBS), upstream regulators and Gene Set Enrichment Analysis (GSEA). NeMO increased bladder mass, relative bladder mass and hyperactivity, and decreased voiding efficiency. In NeMO vs. sham, 831 genes were differentially expressed (adjusted p<0.05) and correlated significantly with at least one physiologic parameter. Gene ontology revealed an enrichment for matrix pathways in the upregulated genes, and for cardiac contraction, oxidative phosphorylation and pyruvate metabolism in downregulated genes. TFBS analysis revealed a differential regulation of up vs downregulated genes, with KLF4 strongly associated with the downregulated genes. Downregulated genes of Human bladder obstruction were also associated with the TFBS of KLF4. GSEA of the NeMO gene set confirmed the DAVID results, but also showed a cluster of cytokine activation genes. In human bladder underactive obstruction, cytokines were also highly upregulated. The common cytokine pathway upregulation provided an example of the use of RNAseq for uncovering potential new therapeutic targets. As TNF and the innate immune pathways were strongly implicated in both human and mouse, and TNF is produced by macrophages, we depletion macrophages with clodronate (CL) during NeMO. Although CL did not block hypertrophy, it significantly decreased NeMO-induced hyperactive voiding (p<0.01) and increased voiding efficiency (p<0.05). The expression of several cytokines/chemokines correlated significantly with bladder functional parameters such as residual volumes, and hyperactivity. Conclusions: Gene expression signatures of NeMO were consistent with human bladder obstruction, supporting the use of the nerve-sparing mouse obstruction model for therapeutic exploration.

show abstract

Non-invasive voiding assessment in conscious mice

Cited by 6 publications

References 45 publications

DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF

DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF

Establishment of an overactive bladder model in mice

Human - murine concordance of molecular signatures in nerve-sparing murine partial bladder outlet obstruction (NeMO)

Contact Info

Product

Resources

About