Contractile function of detrusor smooth muscle from children with posterior urethral valves – The role of fibrosis

Johal, Navroop; Cao, Kevin; Arthurs, Callum; Millar, Michael; Thrasivoulou, Christopher; Ahmed, Aamir; Jabr, Rita I.; Wood, Dan; Cuckow, Peter; Fry, Christopher

doi:10.1016/j.jpurol.2020.11.001

Cited by 8 publications

(10 citation statements)

References 34 publications

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“…Detrusor muscle from human paediatric patients with normally-functioning bladders generate atropine-resistant and purinergic-dependent EFS contractions that diminish to the adult phenotype after several years (Johal et al 2014). Similar magnitude contractions are present in tissue from boys born with pBOO due to the congential condition of posterior urethral valves (Johal et al, 2021). This mirrors equivalent data from a fetal sheep model of pBOO (Thiruchelvam et al, 2003) so that a purinergic component of neurotransmission is present in pre-and post-natal development before disappearing in the normal adult bladder.…”

Section: Purinergic Pathophysiology and Detrusor Contractionsupporting

confidence: 74%

Purinergic signalling in the urinary bladder – When function becomes dysfunction

Fry

McCloskey

2021

Autonomic Neuroscience

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Section: Purinergic Pathophysiology and Detrusor Contractionsupporting

confidence: 74%

Purinergic signalling in the urinary bladder – When function becomes dysfunction

Fry

McCloskey

2021

Autonomic Neuroscience

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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: 81%

“…Of significance in the context of fibrosis development in paediatric human bladders subjected to different congenital anomalies is that the pattern of protein expression varies greatly. Thus, in exstrophy tissue, MMP-7, β-catenin and c-Myc all showed reduced expression [ 18 ], whereas in detrusor from obstructed bladders MMP-7 and cyclin-D1 expression were increased, but β-catenin and c-Myc were reduced [ 19 ]. The major conclusion that may be drawn is that although tissues from all bladder anomalies developed fibrosis, the cellular pathways responsible were different.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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“…In historic human samples from PUV bladders, muscular hypertrophy was dominant, with little or no fibrosis present [ 24 , 25 ]. However, in a very recent study with detrusor samples from children with PUV, increased expression of matrix metalloproteinase 7 and cyclin-D1 suggested that there was cellular remodelling with accumulation of extracellular matrix, including collagen and replacement of smooth muscle cells [ 26 ]. In addition to the fibrotic remodelling in the bladder, increased urethral resistance causes hypertrophy of the muscular bladder wall ( Figure 1 ), which postnatally leads to a small capacity, hypercontractile bladder.…”

Section: Pathophysiology Of Chronic Kidney Disease In Posterior Ureth...mentioning

confidence: 99%

Chronic Kidney Disease in Boys with Posterior Urethral Valves–Pathogenesis, Prognosis and Management

Klaus

Lange-Sperandio

2022

Biomedicines

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Posterior urethral valves (PUV) are the most common form of lower urinary tract obstructions (LUTO). The valves can be surgically corrected postnatally; however, the impairment of kidney and bladder development is irreversible and has lifelong implications. Chronic kidney disease (CKD) and bladder dysfunction are frequent problems. Approximately 20% of PUV patients will reach end-stage kidney disease (ESKD). The subvesical obstruction in PUV leads to muscular hypertrophy and fibrotic remodelling in the bladder, which both impair its function. Kidney development is disturbed and results in dysplasia, hypoplasia, inflammation and renal fibrosis, which are hallmarks of CKD. The prognoses of PUV patients are based on prenatal and postnatal parameters. Prenatal parameters include signs of renal hypodysplasia in the analysis of fetal urine. Postnatally, the most robust predictor of PUV is the nadir serum creatinine after valve ablation. A value that is below 0.4 mg/dl implies a very low risk for ESKD, whereas a value above 0.85 mg/dl indicates beneficial kidney outcome. Experimental urinary markers such as MCP-1 and TGF-β, as well as microalbuminuria, indicate progression to CKD. Until now, prenatal intervention may improve survival but yields no renal benefit. The management of PUV patients includes control of bladder dysfunction and CKD treatment to slow down progression by controlling hypertension, proteinuria and infections. In kidney transplantation, aggressive bladder management is essential to ensure optimal graft survival.

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Contractile function of detrusor smooth muscle from children with posterior urethral valves – The role of fibrosis

Cited by 8 publications

References 34 publications

Purinergic signalling in the urinary bladder – When function becomes dysfunction

Purinergic signalling in the urinary bladder – When function becomes dysfunction

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

Chronic Kidney Disease in Boys with Posterior Urethral Valves–Pathogenesis, Prognosis and Management

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