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Role of Caveolae and miRNAs in Regulation of Urinary Bladder Function

Karbalaei, Mardjaneh LU (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:
author
supervisor
opponent
  • Professor Tobin, Gunnar, Göteborgs Universitet
organization
publishing date
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
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
2014-11-25 11:38:33
date last changed
2016-09-19 08:44:45
@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},
  pages        = {70},
  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},
}