Functional, histological and molecular characteristics of human exstrophy detrusor

Johal, Navroop; Arthurs, Callum; Cuckow, Peter; Cao, Kevin; Wood, Dan; Ahmed, Aamir; Fry, Christopher

doi:10.1016/j.jpurol.2018.12.004

Cited by 17 publications

(18 citation statements)

References 28 publications

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“…Overall, this complex picture of contractile decline is different from that observed in human detrusor from other congenital anomalies such as bladder exstrophy or posterior urethral valves [ 18 , 19 ]. In these cases, replacement of detrusor muscle by connective tissue was also deemed to be a major factor but, crucially, functional denervation was not evident.…”

Section: Discussionmentioning

confidence: 77%

“…Tissue arrays were each made from 25 to 30 collections of paraffin-embedded tissue cores (1 mm diameter) and sections (5 µM) cut for antibody labelling. A BondmaX™ automated system (Leica BioSystems, Seoul, Korea) was an automated staining platform [ 18 , 19 ], and antibodies were optimised for concentration, pH-dependence and antigen retrieval. Those used, as per manufacturer’s instructions, were: β-catenin (ab22656, Abcam, Cambridge, UK), c-Myc (Novacastra/Leica Biosystems), cyclin-D1 (sc 718, Santa Cruz, Santa Cruz, CA, USA) and MMP-7 (ab4044, Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…For expression analyses, each section was imaged with a TCS SP8 confocal system (Leica) at 63x magnification. Then, from five regions under a further 6x times digital magnification, the number of pixels at each fluorophore channel was measured using a macro compiled within Huygens Professional software (SVI, Hilversum, The Netherlands) to measure individual channel intensities [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…These processes are augmented by the release of Wnt -ligand proteins mediated by transcription factors such as β-catenin, c-Myc and cyclin-D1. Modulation of Wnt -ligand regulation occurs in another congenital human bladder anomaly, exstrophy, by identification of coding changes [ 17 ] and immunohistochemical mapping of transcription factors [ 18 ]. A further objective of this study was to identify the potential role of Wnt -ligand mediated pathways in the development of fibrosis in the paediatric neurogenic neuropathic bladder.…”

Section: Introductionmentioning

confidence: 99%

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Contractile and Structural Properties of Detrusor from Children with Neurogenic Lower Urinary Tract Dysfunction

Johal

Cao

Xie

et al. 2021

Biology

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Neurogenic lower urinary tract (NLUT) dysfunction in paediatric patients can arise after congenital or acquired conditions that affect bladder innervation. With some patients, urinary tract dysfunction remains and is more difficult to treat without understanding the pathophysiology. We measured in vitro detrusor smooth muscle function of samples from such bladders and any association with altered Wnt-signalling pathways that contribute to both foetal development and connective tissue deposition. A comparator group was tissue from children with normally functioning bladders. Nerve-mediated and agonist-induced contractile responses and passive stiffness were measured. Histology measured smooth muscle and connective tissue proportions, and multiplex immunohistochemistry recorded expression of protein targets associated with Wnt-signalling pathways. Detrusor from the NLUT group had reduced contractility and greater stiffness, associated with increased connective tissue content. Immunohistochemistry showed no major changes to Wnt-signalling components except down-regulation of c-Myc, a multifunctional regulator of gene transcription. NLUT is a diverse term for several diagnoses that disrupt bladder innervation. While we cannot speculate about the reasons for these pathophysiological changes, their recognition should guide research to understand their ultimate causes and develop strategies to attenuate and even reverse them. The role of changes to the Wnt-signalling pathways was minor.

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Section: Discussionmentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Contractile and Structural Properties of Detrusor from Children with Neurogenic Lower Urinary Tract Dysfunction

Johal

Cao

Xie

et al. 2021

Biology

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“…Similar changes to reduced active contractile responses, accompanied by an increased proportion of connective tissue and elastic modulus have also been reported in human detrusor from bladders with contractile dysfunction. 24 We were careful when measuring elastic modulus to always use data from the first stretch protocol, as passive stiffness changes with repeated stretch protocols. 25 A limitation of the study is that it was not possible to match connective tissue content with either passive stiffness or active contractile performance for every preparation, due to the requirement to dissect two sufficient preparations from each small mouse bladder for active tension and passive tension/ATP release experiments.…”

Section: Discussionmentioning

confidence: 99%

Stretch‐ and carbachol‐induced ATP release from bladder wall preparations of young and aged mice

Nishikawa

Chakrabarty

Kitney

et al. 2020

Neurourology and Urodynamics

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Aims Bladder wall stretch increases tissue tension and releases adenosine 5'‐triphosphate (ATP) as part of a transduction process to sense bladder filling. Aging is associated with bladder fibrosis to produce a stiffer bladder wall: this may augment ATP release and contribute to age‐dependent urgency. Muscarinic agonists also release ATP and present a potential target for antimuscarinic agents, but its age‐dependency is unknown. This study aimed, in young and old mice, to: (a) quantify the relationship between bladder wall stiffness and stretch‐dependent ATP release and; (b) characterize muscarinic agonist‐dependent release. Methods ATP release from young (9‐12 weeks) and aged (24 months) mouse bladder wall was measured in vitro, with a luciferin‐luciferase assay, after stretch or carbachol exposure. Bladder wall stiffness, measured simultaneously during stretch, was compared to histological proportions of connective tissue and detrusor muscle. Results With young mice, stretch‐activated ATP release required an intact mucosa and was positively associated with wall stiffness. ATP release by carbachol was about four‐fold greater compared to stretch. With aged mice: ATP release varied a hundred‐fold and no association with stiffness; carbachol release diminished; connective tissue and mucosa thickness increased. Conclusions With young mice, stretch, or muscarinic agonists potently induce bladder wall ATP release. Stretch‐dependent release is proportional to bladder wall stiffness, independent of the extent of stretch. With aged mice dependence of stretch‐activated ATP release with stiffness was lost. The huge variability of release suggests that aged mice do not form a homogenous cohort and may underlie the heterogeneity in bladder filling sensations.

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New targets for overactive bladder—ICI‐RS 2109

Fry

Chakrabarty

Hashitani

et al. 2019

Neurourology and Urodynamics

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Aims. To review evidence for novel drug targets that can manage overactive bladder symptoms. Methods. A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterise their use to treat overactive bladder. Results. Five classes of agents or cellular pathways were considered. 1) Cyclic nucleotide-dependent (cAMP and cGMP) pathways that modulate ATP release from motor nerves and urothelium. 2) Novel targets for beta-3 agonists, including the bladder wall vasculature and muscularis mucosa. 3) Several TRP channels (TRPV1, TRPV4, TRPA1, TRPM4) and their modulators in affecting detrusor overactivity. 4) small conductance Ca 2+activated K + channels and their influence on spontaneous contractions. 5) antifibrosis agents that act to modulate directly or indirectly the TGF-beta pathway-the canonical fibrosis pathway. Conclusions. Specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above potential agents are distributed among most organ systems. The tasks are to determine: more detail of the pathological changes that occur in the overactive bladder and; how specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.

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Functional, histological and molecular characteristics of human exstrophy detrusor

Cited by 17 publications

References 28 publications

Contractile and Structural Properties of Detrusor from Children with Neurogenic Lower Urinary Tract Dysfunction

Contractile and Structural Properties of Detrusor from Children with Neurogenic Lower Urinary Tract Dysfunction

Stretch‐ and carbachol‐induced ATP release from bladder wall preparations of young and aged mice

New targets for overactive bladder—ICI‐RS 2109

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