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 3

Regulation of mRNA and miRNA expression reflects similar biological processes.

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Regulation of mRNA and miRNA expression reflects similar biological proc...
(A) Hierarchical clustering of log2 fold changes of mRNA (y axis) encoding muscle-specific proteins, growth factors, proteins involved in Ca2+ homeostasis, and regulators of hypertrophy and fibrosis in BOO patients: obstructed patients with detrusor overactivity (DO), obstructed patients without detrusor overactivity (BO), obstructed patients with underactive bladders (UA), and controls (C) (x axis). (B) Hierarchical clustering of selected muscle-specific miRNAs and miRNAs regulated during hypertrophy and fibrosis. Smooth muscle-specific mRNAs and miRNAs decreased in BO and UA, but increased in DO samples; profibrotic transcripts and miRNAs were increased in BO and UA biopsies.