Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.

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. Her...

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Autores principales:	Mari Ekman, Anirban Bhattachariya, Diana Dahan, Bengt Uvelius, Sebastian Albinsson, Karl Swärd
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3015e463fca24155b6144e9cc6d08fc6
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spelling	oai:doaj.org-article:3015e463fca24155b6144e9cc6d08fc62021-11-18T08:42:40ZMir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.1932-620310.1371/journal.pone.0082308https://doaj.org/article/3015e463fca24155b6144e9cc6d08fc62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24340017/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Recent 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.Mari EkmanAnirban BhattachariyaDiana DahanBengt UveliusSebastian AlbinssonKarl SwärdPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e82308 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mari Ekman Anirban Bhattachariya Diana Dahan Bengt Uvelius Sebastian Albinsson Karl Swärd Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
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.
format	article
author	Mari Ekman Anirban Bhattachariya Diana Dahan Bengt Uvelius Sebastian Albinsson Karl Swärd
author_facet	Mari Ekman Anirban Bhattachariya Diana Dahan Bengt Uvelius Sebastian Albinsson Karl Swärd
author_sort	Mari Ekman
title	Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
title_short	Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
title_full	Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
title_fullStr	Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
title_full_unstemmed	Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
title_sort	mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/3015e463fca24155b6144e9cc6d08fc6
work_keys_str_mv	AT mariekman mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness AT anirbanbhattachariya mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness AT dianadahan mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness AT bengtuvelius mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness AT sebastianalbinsson mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness AT karlsward mir29repressioninbladderoutletobstructioncontributestomatrixremodelingandalteredstiffness
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Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.

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