Tumor Necrosis Factor-α Initiates miRNA-mRNA Signaling Cascades in Obstruction-Induced Bladder Dysfunction.

Köck, Ivonne; Hashemi Gheinani, Ali; Baumgartner, Ulrich; Vassella, Erik; Bruggmann, Rémy; Burkhard, Fiona C.; Monastyrskaya-Stäuber, Katia (2018). Tumor Necrosis Factor-α Initiates miRNA-mRNA Signaling Cascades in Obstruction-Induced Bladder Dysfunction. The American journal of pathology, 188(8), pp. 1847-1864. Elsevier 10.1016/j.ajpath.2018.05.008

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Bladder outlet obstruction (BOO) and the ensuing clinical lower urinary tract dysfunction are common in elderly patients. BOO is accompanied by urodynamic changes in bladder function and leads to organ fibrosis and ultimately loss of contractility. Comprehensive transcriptome analysis of bladder samples from human patients with different urodynamically defined phenotypes of BOO revealed tumor necrosis factor (TNF)-α as the top upstream signaling pathway regulator. Herein, we validated next-generation sequencing and pathway analysis in cell-based models using bladder smooth muscle and urothelial cells exposed to TNF-α. miRNA profiling and transcriptome analysis of TNF-α-treated bladder smooth muscle cells revealed striking similarities with human BOO. Using a comparative approach, TNF-specific and TNF-independent pathways were delineated in human biopsy specimens. Concomitant down-regulation of smooth muscle cell-specific miRNAs and smooth muscle markers after TNF-α treatment was in accordance with the loss of contractility in humans in advanced obstruction-induced bladder remodeling. The expression levels of four abundant TNF-regulated miRNAs were modulated; the compensatory up-regulation of miR-199a-5p reduced NF-κB signaling. Essential hubs of TNF-α signaling pathways mitogen-activated protein kinase kinase kinase (apoptosis signal-regulating kinase 1) and IKBKB (IκB kinase β) were targeted by miR-199a-5p. miR-199a-5p might be part of a negative feedback loop, reducing the impact of TNF, whereas its down-regulation in acontractile bladders from BOO patients advances the disease. The compensatory up-regulation of miR-199a-5p together with TNF-α inhibition may be therapeutically beneficial.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

UniBE Contributor:

Köck, Ivonne; Hashemi Gheinani, Ali; Baumgartner, Ulrich; Burkhard, Fiona C. and Monastyrskaya-Stäuber, Katia

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1525-2191

Publisher:

Elsevier

Language:

English

Submitter:

Laetitia Hayoz

Date Deposited:

04 Jul 2018 10:17

Last Modified:

25 Jul 2018 01:32

Publisher DOI:

10.1016/j.ajpath.2018.05.008

PubMed ID:

29920227

BORIS DOI:

10.7892/boris.118235

URI:

https://boris.unibe.ch/id/eprint/118235

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