Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction
Ali Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, Katia Monastyrskaya
Ali Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, Katia Monastyrskaya
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Research Article Aging Muscle biology

Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction

Abstract

Bladder outlet obstruction (BOO) induces significant organ remodeling, leading to lower urinary tract symptoms accompanied by urodynamic changes in bladder function. Here, we report mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients’ miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and NO signaling pathways, and hypertrophic PI3K/AKT signaling pathways. AP-1 and NFkB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Molecular changes in BOO suggest an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.

Authors

Ali Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, Katia Monastyrskaya

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Figure 9

Regulatory role of miRNAs and their targets in different states of BOO.

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Regulatory role of miRNAs and their targets in different states of BOO. ...
(A) Number of abundant miRNAs used for pathway analysis. miRNAs had at least 400 reads in control group and were significantly (P < 0.05) regulated in their data set (>± 1.5-fold change). The number of abundant miRNAs progressively increased between BOO states: 9 for DO, 23 for BO, and 30 for UA. (B) Number of pathways built using miRNA targets. Pathways are significant (P < 0.05), with a Z score prediction. Regulated abundant miRNAs may target a progressively increasing number of pathway elements in DO, BO, and UA. (C) The abundances of individual miRNAs calculated as percentages of individual read counts in the BOO patient miRNA library. The relative content of the most abundant regulated miRNAs is shown. (D) Force-directed graph visualizing direct interaction of 12 miRNAs with 66 mRNA targets represented among pathway elements of miRNA-regulated pathways. Node color is indicative of direction of regulation, and node size is proportional to the absolute value of their log2 fold changes compared with controls. Downregulated miRNAs target the majority of important pathway elements in BOO. C, controls; DO, obstructed patients with detrusor overactivity; BO, obstructed patients without detrusor overactivity; UA, obstructed patients with underactive bladders.