Role of Caveolae and miRNAs in Regulation of Urinary Bladder Function
(2014) In Lund University Faculty of Medicine Doctoral Dissertation Series 2014:126.- Abstract
- The urinary bladder is responsible for storage and expulsion of urine. Proper urination depends on an ability of the
bladder to adjust to increasing volume and to contract during micturition. A disturbance of bladder contractility
may affect continence. In the present thesis I have used genetic, biochemical and physiological approaches to
examine the role of caveolae and mircoRNAs in bladder function.
Caveolae are 60-80 nm large membrane invaginations present in a variety of cell types including smooth muscle.
A classical view is that caveolae organize the cell membrane and thereby regulate cell signalling. The proteins
caveolin-1 and cavin-1 are essential for biogenesis of caveolae in... (More) - The urinary bladder is responsible for storage and expulsion of urine. Proper urination depends on an ability of the
bladder to adjust to increasing volume and to contract during micturition. A disturbance of bladder contractility
may affect continence. In the present thesis I have used genetic, biochemical and physiological approaches to
examine the role of caveolae and mircoRNAs in bladder function.
Caveolae are 60-80 nm large membrane invaginations present in a variety of cell types including smooth muscle.
A classical view is that caveolae organize the cell membrane and thereby regulate cell signalling. The proteins
caveolin-1 and cavin-1 are essential for biogenesis of caveolae in many cell types. The first aim of this thesis was
to address the significance of caveolae for detrusor function by using caveolin-1 and cavin-1 knockout mice.
Deletion of either caveolin-1 or cavin-1 led to lack of caveolae, reduced muscarinic and depolarisation-induced
contraction and impaired neuro-effector transmission. Lack of cavin-1 was moreover associated with bladder
hypertrophy. In vivo micturition patterns were however largely similar, arguing in favour of compensatory
mechanisms during normal voiding. In all, my findings show that the phenotypic overlap of two distinct knockout
models, both of which lack detrusor caveolae, is considerable. This establishes an important role of these
organelles for detrusor function.
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by mRNA degradation and
translational repression. The biogenesis of most miRNAs depends on the enzyme Dicer. To investigate the role of
miRNAs in the urinary bladder I used two animal models: 1) smooth muscle-specific Dicer knockout mice and 2)
surgically induced bladder outlet obstruction, BOO. Depletion of miRNAs resulted in altered micturition pattern,
impaired contractility and reduced twitches in response to electrical field stimulation. Dicer deletion was
associated with reduced expression of L-type Ca2+ channels and reduced expression of the differentiation markers
desmin and calponin. Partial outlet obstruction, on the other hand, resulted in altered expression of 50 miRNAs,
supporting a role of this class of RNAs in bladder pathology. Most impressive was a five to ten-fold increase in
expression of miR-132/212. Transcription factor binding site analysis pointed to the involvement of Ahr and Creb
in miR-132/212 induction. Targets of these miRNAs correlated inversely with the miR-132/212 levels.
Overexpression of antimirs and mimics for miR-132/212 caused reciprocal changes in cell proliferation. Taken
together, my findings demonstrate that miRNAs play a key role for normal detrusor function and argue that they
regulate gene expression and cell proliferation following obstruction. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4810404
- author
- Karbalaei, Mardjaneh LU
- supervisor
-
- Karl Swärd LU
- Per Hellstrand LU
- Bengt-Olof Nilsson LU
- Catarina Rippe LU
- opponent
-
- Professor Tobin, Gunnar, Göteborgs Universitet
- organization
- publishing date
- 2014
- type
- Thesis
- publication status
- published
- subject
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2014:126
- pages
- 70 pages
- publisher
- Cellular Biomechanics
- defense location
- Segerfalksalen
- defense date
- 2014-11-14 09:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-055-5
- language
- English
- LU publication?
- yes
- id
- ae2d3f49-6970-4426-a295-3b9902fd2ee5 (old id 4810404)
- date added to LUP
- 2016-04-01 13:00:16
- date last changed
- 2019-05-22 04:56:21
@phdthesis{ae2d3f49-6970-4426-a295-3b9902fd2ee5,
abstract = {{The urinary bladder is responsible for storage and expulsion of urine. Proper urination depends on an ability of the<br/><br>
bladder to adjust to increasing volume and to contract during micturition. A disturbance of bladder contractility<br/><br>
may affect continence. In the present thesis I have used genetic, biochemical and physiological approaches to<br/><br>
examine the role of caveolae and mircoRNAs in bladder function.<br/><br>
Caveolae are 60-80 nm large membrane invaginations present in a variety of cell types including smooth muscle.<br/><br>
A classical view is that caveolae organize the cell membrane and thereby regulate cell signalling. The proteins<br/><br>
caveolin-1 and cavin-1 are essential for biogenesis of caveolae in many cell types. The first aim of this thesis was<br/><br>
to address the significance of caveolae for detrusor function by using caveolin-1 and cavin-1 knockout mice.<br/><br>
Deletion of either caveolin-1 or cavin-1 led to lack of caveolae, reduced muscarinic and depolarisation-induced<br/><br>
contraction and impaired neuro-effector transmission. Lack of cavin-1 was moreover associated with bladder<br/><br>
hypertrophy. In vivo micturition patterns were however largely similar, arguing in favour of compensatory<br/><br>
mechanisms during normal voiding. In all, my findings show that the phenotypic overlap of two distinct knockout<br/><br>
models, both of which lack detrusor caveolae, is considerable. This establishes an important role of these<br/><br>
organelles for detrusor function.<br/><br>
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by mRNA degradation and<br/><br>
translational repression. The biogenesis of most miRNAs depends on the enzyme Dicer. To investigate the role of<br/><br>
miRNAs in the urinary bladder I used two animal models: 1) smooth muscle-specific Dicer knockout mice and 2)<br/><br>
surgically induced bladder outlet obstruction, BOO. Depletion of miRNAs resulted in altered micturition pattern,<br/><br>
impaired contractility and reduced twitches in response to electrical field stimulation. Dicer deletion was<br/><br>
associated with reduced expression of L-type Ca2+ channels and reduced expression of the differentiation markers<br/><br>
desmin and calponin. Partial outlet obstruction, on the other hand, resulted in altered expression of 50 miRNAs,<br/><br>
supporting a role of this class of RNAs in bladder pathology. Most impressive was a five to ten-fold increase in<br/><br>
expression of miR-132/212. Transcription factor binding site analysis pointed to the involvement of Ahr and Creb<br/><br>
in miR-132/212 induction. Targets of these miRNAs correlated inversely with the miR-132/212 levels.<br/><br>
Overexpression of antimirs and mimics for miR-132/212 caused reciprocal changes in cell proliferation. Taken<br/><br>
together, my findings demonstrate that miRNAs play a key role for normal detrusor function and argue that they<br/><br>
regulate gene expression and cell proliferation following obstruction.}},
author = {{Karbalaei, Mardjaneh}},
isbn = {{978-91-7619-055-5}},
issn = {{1652-8220}},
language = {{eng}},
publisher = {{Cellular Biomechanics}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{Role of Caveolae and miRNAs in Regulation of Urinary Bladder Function}},
volume = {{2014:126}},
year = {{2014}},
}