Dataset Information

Detrusor induction of miR-132/212 following bladder outlet obstruction: association with MeCP2 repression and cell viability.

ABSTRACT: The microRNAs (miRNAs) miR-132 and miR-212 have been found to regulate synaptic plasticity and cholinergic signaling and recent work has demonstrated roles outside of the CNS, including in smooth muscle. Here, we examined if miR-132 and miR-212 are induced in the urinary bladder following outlet obstruction and whether this correlates with effects on gene expression and cell growth. Three to seven-fold induction of miR-132/212 was found at 10 days of obstruction and this was selective for the detrusor layer. We cross-referenced putative binding sites in the miR-132/212 promoter with transcription factors that were predicted to be active in the obstruction model. This suggested involvement of Creb and Ahr in miR-132/212 induction. Creb phosphorylation (S-133) was not increased, but the number of Ahr positive nuclei increased. Moreover, we found that serum stimulation and protein kinase C activation induced miR-132/212 in human detrusor cells. To identify miR-132/212 targets, we correlated the mRNA levels of validated targets with the miRNA levels. Significant correlations between miR-132/212 and MeCP2, Ep300, Pnkd and Jarid1a were observed, and the protein levels of MeCP2, Pnkd and Ache were reduced after obstruction. Reduction of Ache however closely matched a 90% reduction of synapse density arguing that its repression was unrelated to miR-132/212 induction. Importantly, transfection of antimirs and mimics in cultured detrusor cells increased and decreased, respectively, the number of cells and led to changes in MeCP2 expression. In all, these findings show that obstruction of the urethra increases miR-132 and miR-212 in the detrusor and suggests that this influences gene expression and limits cell growth.

SUBMITTER: Sadegh MK

PROVIDER: S-EPMC4305303 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Detrusor induction of miR-132/212 following bladder outlet obstruction: association with MeCP2 repression and cell viability.

Sadegh Mardjaneh Karbalaei MK Ekman Mari M Krawczyk Katarzyna K Svensson Daniel D Göransson Olga O Dahan Diana D Nilsson Bengt-Olof BO Albinsson Sebastian S Uvelius Bengt B Swärd Karl K

PloS one 20150124 1

The microRNAs (miRNAs) miR-132 and miR-212 have been found to regulate synaptic plasticity and cholinergic signaling and recent work has demonstrated roles outside of the CNS, including in smooth muscle. Here, we examined if miR-132 and miR-212 are induced in the urinary bladder following outlet obstruction and whether this correlates with effects on gene expression and cell growth. Three to seven-fold induction of miR-132/212 was found at 10 days of obstruction and this was selective for the de ...[more]

PMID: 25617893

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Project description:PurposeThis study was conducted to evaluate the efficacy of bladder outlet surgery in patients with detrusor underactivity (DU) and to identify factors associated with successful outcomes.MethodsWe conducted a retrospective review of men diagnosed with DU in urodynamic studies who underwent bladder outlet surgery for lower urinary tract symptoms between May 2018 and April 2023. The International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry (UFM), and multichannel urodynamic studies were administered. Successful treatment outcomes were defined as either an IPSS improvement of at least 50% or the regaining of spontaneous voiding in patients urethral catheterization prior to surgery.ResultsThe study included 93 male patients. Men diagnosed with significant or equivocal bladder outlet obstruction (BOO) experienced significant postoperative improvements in IPSS (from 20.6 to 6.0 and from 17.4 to 6.5, respectively), maximum urine flow rate (from 5.0 mL/sec to 14.4 mL/sec and from 8.8 mL/sec to 12.2 mL/sec, respectively) and voiding efficiency (from 48.8% to 86.0% and from 61.2% to 85.1%, respectively). However, in the group without obstruction, the improvements in IPSS and UFM results were not significant. The presence of detrusor overactivity (odds ratio [OR], 3.152; P=0.025) and preoperative urinary catheterization (OR, 2.756; P=0.040) were associated with favorable treatment outcomes. Conversely, an unobstructed bladder outlet was identified as a negative prognostic factor.ConclusionIn men with DU accompanied by equivocal or significant BOO, surgical intervention to alleviate the obstruction may enhance the IPSS, quality of life, and UFM results. However, those with DU and an unobstructed bladder outlet face a comparatively high risk of treatment failure. Preoperative detrusor overactivity and urinary catheterization are associated with more favorable surgical outcomes. Consequently, active deobstructive surgery should be considered for patients with DU who are experiencing urinary retention.

Project description:Recent work has uncovered a role of the microRNA (miRNA) miR-29 in remodeling of the extracellular matrix. Partial bladder outlet obstruction is a prevalent condition in older men with prostate enlargement that leads to matrix synthesis in the lower urinary tract and increases bladder stiffness. Here we tested the hypothesis that miR-29 is repressed in the bladder in outlet obstruction and that this has an impact on protein synthesis and matrix remodeling leading to increased bladder stiffness. c-Myc, NF-κB and SMAD3, all of which repress miR-29, were activated in the rat detrusor following partial bladder outlet obstruction but at different times. c-Myc and NF-κB activation occurred early after obstruction, and SMAD3 phosphorylation increased later, with a significant elevation at 6 weeks. c-Myc, NF-κB and SMAD3 activation, respectively, correlated with repression of miR-29b and miR-29c at 10 days of obstruction and with repression of miR-29c at 6 weeks. An mRNA microarray analysis showed that the reduction of miR-29 following outlet obstruction was associated with increased levels of miR-29 target mRNAs, including mRNAs for tropoelastin, the matricellular protein Sparc and collagen IV. Outlet obstruction increased protein levels of eight out of eight examined miR-29 targets, including tropoelastin and Sparc. Transfection of human bladder smooth muscle cells with antimiR-29c and miR-29c mimic caused reciprocal changes in target protein levels in vitro. Tamoxifen inducible and smooth muscle-specific deletion of Dicer in mice reduced miR-29 expression and increased tropoelastin and the thickness of the basal lamina surrounding smooth muscle cells in the bladder. It also increased detrusor stiffness independent of outlet obstruction. Taken together, our study supports a model where the combined repressive influences of c-Myc, NF-κB and SMAD3 reduce miR-29 in bladder outlet obstruction, and where the resulting drop in miR-29 contributes to matrix remodeling and altered passive mechanical properties of the detrusor.

Dataset Information

Detrusor induction of miR-132/212 following bladder outlet obstruction: association with MeCP2 repression and cell viability.

Publications

Detrusor induction of miR-132/212 following bladder outlet obstruction: association with MeCP2 repression and cell viability.

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