Changes in aquaporin 1 expression in rat urinary bladder after partial bladder outlet obstruction: preliminary report.
ABSTRACT Aquaporins (AQPs) are membrane proteins that facilitate water movement across biological membranes. AQPs are also called water channels, and they have recently been reported to be expressed in rat and human urothelium. The purposes of this study were to investigate the effect of bladder outlet obstruction (BOO) on the rat urothelium and AQP1 expression in rat urothelium.
Female Sprague-Dawley rats (230-240 g each, n=20) were divided into 2 groups: the sham group (the Con group, n=10) and the partial BOO group (the BOO group, n=10). The BOO group underwent a partial BOO. The expression and cellular localization of AQP1 were determined by performing Western blotting and immunohistochemistry on the rat urinary bladder.
AQP1 immunoreactivity in both the control and the BOO groups was localized in the capillaries, arterioles, and venules of the lamina propria of the urinary bladder. The protein expression of AQP1 was significantly increased in the BOO group.
This study showed that BOO causes a significant increase in the expression of AQP1. This may imply that AQP1 has a functional role in the detrusor instability that occurs in association with BOO.
- SourceAvailable from: Seung Wook Lee[Show abstract] [Hide abstract]
ABSTRACT: Bladder wall thickness (BWT) is reported to be related to detrusor overactivity and bladder outlet obstruction. We investigated the relationship between BWT and the responsiveness of storage symptoms to alpha-blockers in men with lower urinary tract symptoms (LUTS). A total of 74 patients with LUTS were enrolled. International Prostate Symptom Score, uroflowmetry with post-void residual urine volume, and transrectal ultrasonography (TRUS) were investigated. BWT was measured by performing TRUS at the midsagittal plane view, and the average value of BWT at the anterior, dome, and trigone areas was used. After 4 weeks of alpha-blocker medication, patients were reevaluated and divided into two groups. The responder group consisted of patients who reported improvement in the storage symptom subscore of 2 points or more; the non-responder group consisted of patients who reported improvement of less than 2 points. Clinical parameters including BWT were compared between the two groups. A total of 52 patients were followed. BWT was positively correlated with intravesical prostate protrusion (IPP) (9.26±4.99, standardized beta=0.393, p=0.002) and storage symptom subscore (0.35±0.43, standardized beta=0.458, p=0.002). Compared with that in the responder group, BWT was thicker in the non-responder group, and improvement in the storage symptom score was correlated with BWT (0.58±0.09 cm vs. 0.65±0.11 cm, p=0.018) and prostate volume (27.08±16.26 ml vs. 36.44±10.1 ml, p=0.018). BWT was correlated with IPP, the storage symptom subscore, and the responsiveness of storage symptoms to alpha-blockers in LUTS/benign prostatic hyperplasia (BPH) patients. As BWT increased, the responsiveness of storage symptoms to alpha-blocker decreased in LUTS/BPH patients.Korean journal of urology 07/2012; 53(7):487-91.
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ABSTRACT: This study was designed to investigate the effect of detrusor overactivity induced by partial bladder outlet obstruction (BOO) on the expression of aquaporin 1 (AQP1) and caveolin 1 (CAV1) in the rat urinary bladder, and to determine the role of these molecules in detrusor overactivity. Female Sprague-Dawley rats were divided into control (n=30) and experimental (n=30) groups. The BOO group underwent partial BOO, and the control group underwent a sham operation. After 4 weeks, an urodynamic study was performed to measure the contraction interval and contraction pressure. The expression and cellular localization of AQP1 and CAV1 were determined by western blot and immunofluorescence experiments in the rat urinary bladder. In cystometrograms, the contraction interval was significantly lower in the BOO group (2.9±1.5 minutes) than in the control group (6.7±1.0 minutes) (P<0.05). Conversely, the average contraction pressure was significantly higher in the BOO group (21.2±3.3 mmHg) than in the control group (13.0±2.5 mmHg) (P<0.05). AQP1 and CAV1 were coexpressed in the capillaries, arterioles, and venules of the suburothelial layer. AQP1 and CAV1 protein expression was significantly increased in the BOO rats compared to the control rats (P<0.05). Detrusor overactivity induced by BOO causes a significant increase in the expression of AQP1 and CAV1, which were coexpressed in the suburothelial microvasculature. This finding suggests that AQP1 and CAV1 might be closely related to bladder signal activity and may have a functional role in BOO-associated detrusor overactivity.International neurourology journal 12/2013; 17(4):174-9.
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ABSTRACT: Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder that predominantly affects the optic nerve and spinal cord; however, symptomatic brain involvement is not rare and is sometimes an initial manifestation in NMO. In this study, we investigated the characteristic features of patients with NMO with symptomatic brain involvement as the initial manifestation of disease (NMObrain) compared with patients with NMO who presented initially with optic neuritis or myelitis (NMOON/myelitis). We retrospectively reviewed 27 consecutive Korean patients with NMO with aquaporin-4 antibodies. Patients with NMObrain (n=9) initially presented with intractable hiccup/nausea/vomiting and/or encephalopathy at a younger age than the patients with NMOON/myelitis (n=18) (p<0.01). During the disease course, the patients with NMObrain continued to show more frequent symptomatic involvement of the brain than the 18 patients with NMOON/myelitis (p<0.05). At the final visit, the mean age was also significantly lower in patients with NMObrain than in patients with NMOON/myelitis (p<0.01); however, the Expanded Disability Status Scale scores, used to evaluate disease progression, were not different between the two groups. Our study suggests that patients with NMO who present initially with symptomatic brain involvement may have earlier disease onset and become disabled at a younger age compared to patients with typical NMO. Additional large scale prospective studies are warranted.Journal of Clinical Neuroscience 05/2013; · 1.25 Impact Factor
Korean Journal of Urology
Ⓒ The Korean Urological Association, 2010
Korean J Urol 2010;51:281-286
Changes in Aquaporin 1 Expression in Rat Urinary Bladder after
Partial Bladder Outlet Obstruction: Preliminary Report
Sun-Ouck Kim, Seung Hee Song, Kuyoun Ahn1, Dongdeuk Kwon, Kwangsung Park, Soo Bang Ryu
Departments of Urology and 1Anatomy, Sexual Medical Research Center, Chonnam National University Medical School, Gwangju, Korea
Purpose: Aquaporins (AQPs) are membrane proteins that facilitate water movement
across biological membranes. AQPs are also called water channels, and they have re-
cently been reported to be expressed in rat and human urothelium. The purposes of
this study were to investigate the effect of bladder outlet obstruction (BOO) on the rat
urothelium and AQP1 expression in rat urothelium.
Materials and Methods: Female Sprague-Dawley rats (230-240 g each, n=20) were div-
ided into 2 groups: the sham group (the Con group, n=10) and the partial BOO group
(the BOO group, n=10). The BOO group underwent a partial BOO. The expression and
cellular localization of AQP1 were determined by performing Western blotting and im-
munohistochemistry on the rat urinary bladder.
Results: AQP1 immunoreactivity in both the control and the BOO groups was localized
in the capillaries, arterioles, and venules of the lamina propria of the urinary bladder.
The protein expression of AQP1 was significantly increased in the BOO group.
Conclusions: This study showed that BOO causes a significant increase in the ex-
pression of AQP1. This may imply that AQP1 has a functional role in the detrusor in-
stability that occurs in association with BOO.
Key Words: Aquaporins; Urinary bladder; Urethral obstruction; Rats
received 29 January, 2010
accepted 6 April, 2010
Department of Urology, Chonnam
National University Hospital and
Medical School, 8, Hak-dong,
Dong-gu, Gwangju 501-757, Korea
This research was supported by the
Basic Science Research Program
through the National Research
Foundation of Korea (NRF) funded by
the Ministry of Education, Science and
Technology (2009-0069443), grant
CRI09011-1, Chonnam National
University Hospital Research Institute
of Clinical Medicine, and a research
grant from the Research Institute of
Medical Sciences, Chonnam National
With the development of bladder outlet obstruction (BOO),
the bladder undergoes not only morphologic and physio-
logic changes, but also functional and symptomatic chan-
ges. Despite the high prevalence of BOO among older men,
the underlying mechanisms that are responsible for the
bladder dysfunction induced by BOO remain poorly under-
The urothelium was previously considered to be a simple
passive barrier between the urinary tract and urine. Re-
cently the urothelium and suburothelial space have re-
ceived renewed interest because of their possible roles in
the pathophysiology of bladder dysfunction. The urothe-
lium is now understood to be an active organ that plays an
important role in regulating bladder disorders . It has
been shown in some animal models that water transfer can
occur across the urothelium from the bladder to the sys-
temic circulation [2-4]. Those studies suggested that the
urothelium can mediate water and solute transport under
certain circumstances [5-9]. Several studies have shown
that rabbit and guinea pig urinary bladder epithelium con-
tains an aldosterone-stimulated sodium transporter .
This transporter has been identified as an epithelial so-
dium channel (ENaC)  that is known to be responsible
for salt and fluid transport across the epithelia of many tis-
Currently, only limited data are available about AQPs
in the mammalian urinary bladder. Spector et al. recently
reported on the localization of AQP1, 2, and 3 in rat urothe-
lium . They reported the presence and regulation of
AQPs in the urothelium of rats after the rats underwent
24 hours of dehydration and then a water loading test. They
suggested that the AQPs in the urothelium may play a role
Korean J Urol 2010;51:281-286
Kim et al
in epithelial cell volume and in controlling osmolarity, and
they strongly suggested the possibility of bulk water move-
ment across the urothelium. Rubenwolf et al  demon-
strated that AQPs are expressed in cultured urothelium
and they suggested a potential role for AQPs in transur-
othelial water and solute transport in humans. However,
there are currently no studies that have investigated the
expression of AQP in the urothelium of rats after BOO or
the functional activity of these proteins in response to BOO.
AQP1 is expressed widely in mammalian epithelial and en-
dothelial plasma membranes. Primarily, AQP1 functions
as a passive water pore that increases water transport
across cell membranes in response to an osmotic driving
force. Furthermore, some evidence suggests that AQP1 has
an ion channel function that has potential significance to
basic and clinical research involving the regulated control
of water and ion fluxes across membranes . On the basis
of these data, we hypothesized that AQP1 channels may be
further impacted by BOO, which may cause bladder dys-
function, at least in part, by an increase in the urothelial
permeability of ion and water.
The purpose of this study was to investigate the impact
of BOO on AQP1 expression in the rat urinary bladder.
MATERIALS AND METHODS
1. Experimental model
Twenty female Sprague-Dawley rats (230-240 g each) were
divided into 2 groups: the control (Con) group (n=10) and
the BOO group (n=10). The BOO group underwent partial
BOO. The animals were premedicated with xylazine (2.2
mg/kg, IM) and anesthetized with a zolazepam/tiletamine
cocktail (4.4 mg/kg, IM). A midline abdominal incision was
made and the bladder and proximal urethra were dissected
free of the surrounding tissue. To create an intravesical ob-
struction, a PE-90 (polyethylene catheter-90) catheter was
placed beside the proximal urethra and a 3-zero silk liga-
ture was tied around the urethra and catheter. The cathe-
ter was subsequently removed and the abdominal incision
was closed. The control group underwent a sham operation.
Histologic studies were performed on both groups after
three weeks. All the rats were in an overnight fasting state
before the experiments were performed; they were given
a standard diet before that time. The protocol for the animal
surgery was approved by the Ethics Committee of the
Chonnam National University Medical School.
2. Western blotting
The tissue homogenates (30 μg of protein) were separated
by 12% SDS-polyacrylamide gel electrophoresis and the
proteins were then transferred to a PVDF membrane
(Amersham Pharmacia Biotech, Little Chalfont, United
Kingdom). The blots were then washed with Tris-buffered
saline Tween-20 (10 mM Tris-HCl, pH 7.6, 150 mM NaCl,
0.05% Tween-20). The membrane was blocked with 5%
skimmed milk for 1 hour and was then incubated with the
appropriate primary antibody. Monoclonal rabbit anti-
bodies for AQP1 (Chemicon, Temecula, CA, USA) and mo-
noclonal rabbit antibodies for glyceraldehyde 3-phosphate
dehydrogenase (GAPDH) (Sigma, St. Louis, MO, USA)
were used. The membrane was then washed and the anti-
body reactions were detected by using goat anti-rabbit-IgG
conjugated to horseradish peroxidase. The antibody incu-
bations were performed in a 4oC incubator. The bands were
visualized by using enhanced chemiluminescence (Amer-
sham Pharmacia Biotech). GAPDH was used as an internal
control. Densitometry analysis was performed with a stu-
dio Star Scanner and by using the NIH image V1-57 soft-
The bladder tissue was dissected away from both lateral
walls of the bladder. The tissue was placed in 4% paraf-
ormaldehyde fixative for 16 hours and the tissue was then
processed for washing and dehydration. The tissue was
routinely embedded in paraffin, and 6 μm sections were
prepared. The tissues were stained with H&E. Immuno-
histochemistry was performed by using an immunoperoxi-
dase procedure (Vector ABC Kit; Vector Laboratories,
Burlingame, CA, USA). The tissue sections were deparaffi-
nized in xylene, dehydrated in a graded series of ethanol
solutions, rinsed twice in phosphate-buffered saline (PBS),
and then treated with 3% H2O2 in 60% methanol for 30 mi-
nutes to quench the endogenous peroxidase activity. After
washing twice (5 minutes each time) in PBS, the sections
were next incubated for 12 to 14 hours with purified rabbit
antibodies for AQP1 (Chemicon) in PBS with 0.3% bovine
serum albumin. For the negative control, the sections were
incubated in PBS containing only 5% normal goat serum.
4. Immunofluorescence staining
The tissue sections were deparaffinized in xylene, dehy-
drated in a graded series of ethanol solutions, rinsed in
PBS, and then treated with normal goat serum for 30 mi-
nutes to block any nonspecific binding. After washing in
PBS, the sections were incubated with antibodies for AQP1
(Chemicon) in PBS with 0.3% bovine serum albumin for 12
to 14 hours at 4°C. For a negative control, the sections were
incubated in PBS containing only 5% normal goat serum.
The sections were then rinsed in PBS and incubated for 30
minutes with the antirabbit IgG conjugated to fluorescein
(Vector Laboratories). Finally, the tissue sections were ex-
amined and photographed under a fluorescence micro-
scope. The sections were then rinsed 3 times in PBS and
incubated sequentially with the biotinylated secondary
antibody and the ABC reagent, and each incubation was
done for 30 minutes. The sections were then incubated for
5 minutes with the peroxidase substrate solution con-
tained in the kit. At last, the tissue sections were examined
and photographed under a light microscope.
5. Statistical analysis
The results were expressed as the mean±the standard er-
ror (SE). Student’s t- tests were performed for the stat-
Korean J Urol 2010;51:281-286
Aquaporin 1 Expression in Rat Urinary Bladder
FIG. 1. Hematoxylin and eosin (H&E) staining of the urinary bladder tissue in the rats of the Con group and the BOO group. A
significant increase in the smooth muscle content and the submucosal tissues along with relative epithelial thinning were noted in
the BOO group compared with the control group. The horizontal scale bar at the bottom of each figure indicates the magnification
power. Con: control, BOO: bladder outlet obstruction.
FIG. 2. Immunohistochemistry for aquaporin 1 (AQP1) in the rat urinary bladder tissue of the Con group and the BOO group. AQPs
are stained brown via immunolabeling. AQP1 was mainly expressed in the capillaries, arterioles, and venules. The expression of
AQP1 was increased in the BOO group. The horizontal scale bar at the bottom of each figure indicates the magnification power. Con:
control, BOO: bladder outlet obstruction.
istical analysis. Differences were considered significant at
All the animals survived for three weeks after the creation
of a partial BOO. There was no significant difference in
body weight between the 2 groups. The weights (mg) of the
bladders were significantly greater in the BOO group
(640±15.3) than in the control group (125.3±17.6), and this
finding supported the proper creation of BOO (p＜0.05).
1. Bladder histology and anatomical influence
In the control rats, the urothelium consisted of 3-4 layers
of transitional cells and lamina propria. Each micro-
vascular structure was surrounded by scattered smooth
Korean J Urol 2010;51:281-286
Kim et al
FIG. 3. Immunofluorescence labeling
for aquaporin 1 (AQP1) in the rat uri-
nary bladder. AQP1 expression (green)
was noted throughout the capillaries,
venules, and vascular smooth muscle.
The expression of AQP1 was increased
in the BOO group. The horizontal scale
bar at the bottom left of each figure in-
dicates the magnification power. Con:
control, BOO: bladder outlet obstruc-
FIG. 4. Immunoblotting for aquaporin 1 (AQP1) in the rat urinary
bladder. The anti-AQP antibodies recognize the 27 to 29 kDa
bands that correspond to glycosylated AQPs. Anti-GAPDH anti-
body recognizes the 42 kDa band. The expression of AQP1 protein
was significantly increased in the BOO group. The lower panels
denote the means±SEs of the 5 experiments for each condition,
as determined by the densitometry relative to GAPDH. Con: con-
trol, BOO: bladder outlet obstruction, a: p＜0.05.
muscle bundles and connective tissue. The bladder wall of
the BOO animals was thicker than that of the normal
controls. In the BOO group, the histology of the bladder tis-
sue showed relative epithelial thinning and distortion of
the mucosa compared with that of the control. The pro-
portion of bladder smooth muscle was also markedly high-
er in the BOO group than in the control group (Fig. 1).
2. The effect of BOO on the expression of AQP1
AQP1 was mainly expressed in the subepithelial capil-
laries and venules of the lamina propria, including the sub-
urothelial tiny arterioles located just beneath the urothe-
lium. The immunohistochemistry revealed that in terms
of the cellular patterns of labeling, the expression of AQP1
in the control group was similar to that in the BOO group.
However, the immunohistochemistry (Fig. 2) and immuno-
fluorescence staining (Fig. 3) showed a marked increase in
the expression of AQP1 in the BOO group. Western blot
analysis revealed bands for AQP proteins at 28 kDa (Fig.
4). AQP1 protein was recognized in all groups, but there
was a significant increase in AQP1 protein in the BOO
group compared with the control group (p＜0.05) (Fig. 4).
In the present study, AQP1 was significantly increased in
the BOO group. These results suggest that AQPs may play
a role in the bladder dysfunction induced by BOO. This
study sheds light on the possible occurrence of water and
Korean J Urol 2010;51:281-286
Aquaporin 1 Expression in Rat Urinary Bladder
solute movement via AQPs in the rat urinary bladder and
the related changes after BOO.
The incidence of overactive bladder symptoms such as
frequency, urgency, and urge incontinence in men older
than 40 years is estimated to be 16.6% . Symptoms of
an overactive bladder can be the result of detrusor over-
activity or detrusor instability that is induced by a variety
of causes. Detrusor overactivity commonly occurs in associ-
ation with BOO. Detrusor overactivity is thought to be
caused by increased afferent nerve activity, but little is
known about the underlying mechanisms by which BOO
increases the afferent nerve activity . The urothelium
is known to have very low permeability to several urinary
solutes and substrates. It has been found that the composi-
tion of the urine changes during its transport through the
urine passages from the renal pelvis to the urinary bladder,
and this finding has been ascribed to a modifying function
of the urothelium [18,19]. Hibernating bears that can re-
absorb their entire daily urine production during the mon-
ths of winter are a dramatic example of net urothelial water
and solute transport . Araki et al. investigated the role
of ENaC in the bladder dysfunction of male patients who
were clinically diagnosed with BOO . They reported
that in patients with BOO, the ENaC expressed in the hu-
man urinary bladder epithelium and the expressed levels
of ENaC were significantly higher than in patients who did
not have BOO. The authors suggested that the ENaC ex-
pression in the bladder epithelium might be implicated in
the mechanosensory transduction that occurs in the blad-
der afferent pathways, and this induces detrusor instabili-
ty by BOO.
AQPs are a family of transmembrane proteins that
transport water across the cell membrane . AQPs are
expressed in many fluid-containing tissues and they are in-
volved in many physiological mechanisms, including the
transportation of transepithelial fluid, the concentration
of urine, and the secretion of gland fluid . AQP1 was the
first identified member of the family, and it is expressed
at a high rate in water-transporting cells, such as those in
the proximal tubule and the thin descending limb in the
kidney, and in red blood cells . However, AQP1 is also
expressed in vascular smooth muscle cells and vascular en-
dothelial cells where net water movement does not appear
to be important [24,25]. To support the hypothesis of water
movement in the bladder from the subepithelial capillaries
to the lumen, this study investigated the expression of
AQPs with focus on the AQP1 expression in the urinary
bladder. In the current study, AQP1 was mainly expressed
in the capillaries, arterioles, and venules of the urinary
Our findings agree with the results of a previous study
by Spector et al, who showed that AQPs in the genito-
urinary tract urothelium likely play a role in regulating ur-
othelial cell volume and osmolality . They revealed that
dehydrated rats had a significant upregulation of AQP ex-
pression, and this finding provides presumptive evidence
that AQPs are involved in water and solute transport
across the urothelium . Rubenwolf et al demonstrated
the expression of AQPs in cultured human urothelial cells,
and they suggested that AQPs play a potential role in tran-
surothelial water and solute transport in the human blad-
der . It has been reported that AQP1 is abundant in a
variety of tissues, and the tissues that express AQP1 ex-
hibit high water permeability and a high osmotic urine con-
centration, gall secretion, formation of cerebrospinal fluid,
and spermatozoa concentration . Lu et al recently re-
ported that AQP1 is expressed in male reproductive organs
such as the rete testis, vas deference, prostate, and seminal
vesicle , and this finding provides valuable information
on the role of AQP1 in water transport to regulate water
homeostasis in male reproductive physiology. The rete tes-
tis is the initial segment of the male reproductive tract and
has a large vascular surface area. The rete testis alters the
nature of the fluid produced by the seminiferous tubule for
making more homogeneous sperm . AQP1 has been ob-
served in the rete testis and a significant change in water
content was found in AQP1 knockout mice, which indicates
that this water channel does indeed play an exclusive role
in water transport for forming the rete testis fluid and
sperm transit .
No studies to date have investigated the expression of the
AQP family members in the urinary bladder of the BOO rat
model or the changes in the functional activity of these pro-
teins in response to BOO. In the present study, the ex-
pression of AQP1 was significantly affected by BOO. These
findings suggest that AQPs are influenced by the bladder
dysfunction induced by anatomical changes such as BOO.
One of the possible reasons behind this influence on the ex-
pression of AQP is believed to be due to the significance of
the location of the AQP expression at the suburothelial
space immediately below the basal lamina of the epithe-
lium, which is well supplied by microvasculature (AQP1).
Our results may suggest that BOO leads to a significant up-
regulation of AQP1 expression, which provides presump-
tive evidence that AQPs are involved in the bladder dys-
function induced by BOO. This bladder dysfunction prob-
ably occurs via modification of the urothelial water and sol-
ute composition. The limitation of this study is that we did
not fully unveil the precise functional activity of AQP1, al-
though we did show the changes in the expression of AQP1
in the BOO rat urinary bladder. Further studies are needed
to investigate the expression and localization of all the AQP
family members in the urinary bladder and their func-
tional role in the underlying mechanisms of bladder patho-
BOO causes a significantly increased expression of AQP1
in the rat urinary bladder. This may imply that AQPs have
a functional role in the bladder dysfunction that occurs in
association with BOO. Further study is needed to clarify
the exact functional role of the different AQPs in the uri-
Korean J Urol 2010;51:281-286
Kim et al
Conflicts of Interest
The authors have nothing to disclose.
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