Functional and Molecular Characterization of Hyposensitive Underactive Bladder Tissue and Urine in Streptozotocin-Induced Diabetic Rat

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Abstract

Background

The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats.

Methodology/Principal Findings

Diabetes mellitus was induced with a single dose of 45 mg/kg STZ Intraperitoneally (i.p) in female Sprague-Dawley rats. Continuous cystometrogram were performed on control rats and STZ treated rats at week 4 or 12 under urethane anesthesia. Bladder was then harvested for histology, expression of EP receptors and NGF by western blotting, PGE2 levels by ELISA, and detection of apoptosis by TUNEL staining. In addition, 4-hr urine was collected from all groups for urine levels of PGE2, and NGF assay. DM induced progressive increase of bladder weight, urine production, intercontraction interval (ICI) and residual urine in a time dependent fashion. Upregulation of Prostaglandin E receptor (EP)1 and EP3 receptors and downregulation of NGF expression, increase in urine NGF and decrease levels of urine PGE2 at week 12 was observed. The decrease in ICI by intravesical instillation of PGE2 was by 51% in control rats and 31.4% in DM group at week 12.

Conclusions/Significance

DM induced hyposensitive underactive bladder which is characterized by increased inflammatory reaction, apoptosis, urine NGF levels, upregulation of EP1 and EP3 receptors and decreased bladder NGF and urine PGE2. The data suggest that EP3 receptor are potential targets in the treatment of diabetes induced underactive bladder.

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Most cited references 37

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International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes.

S. Narumiya, Robert E Coleman, Jennifer Smith (1994)

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Diabetic bladder dysfunction: current translational knowledge.

Firouz Daneshgari, Guiming Liu, Lori A. Birder … (2009)

Diabetes mellitus, a metabolic disorder caused by an absolute or relative deficiency of insulin, is a debilitating and costly disease with multiple serious complications. Lower urinary tract complications are among the most common complications of diabetes mellitus. The most common, bothersome lower urinary tract complication of diabetes mellitus is diabetic cystopathy or diabetic bladder dysfunction. We reviewed the current translational knowledge of diabetic bladder dysfunction. We performed a search of the English literature through PubMed. The key words used were diabetes and bladder dysfunction or cystopathy. Our data and perspective are provided for consideration of the future direction of research. Despite traditional recognition of diabetic bladder dysfunction as a voiding problem characterized by poor emptying and overflow incontinence, recent clinical and experimental evidence indicate storage problems such as urgency and urge incontinence in diabetes mellitus cases. Recent experimental evidence from studies of diabetic bladder dysfunction in small animal models of diabetes mellitus show a temporal effect on diabetic bladder dysfunction. Early phase diabetes mellitus causes compensated bladder function and the late phase causes decompensated bladder function. The temporal theory could plausibly provide the scientific road map to correlate clinical and experimental findings, and identify the role of mechanisms such as polyuria, hyperglycemia, oxidative stress, autonomic neuropathy and decompensation of the bladder contractile apparatus in the creation of clinical and experimental manifestations of diabetic bladder dysfunction. Diabetic bladder dysfunction includes time dependent manifestations of storage and emptying problems. Identifying mechanistic pathways would lead to the identification of therapeutic intervention.

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Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.

Naoki Yoshimura, William C de Groat (1999)

The properties of bladder afferent neurons in L6 and S1 dorsal root ganglia of adult rats were evaluated after chronic bladder inflammation induced by 2 week treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp recordings revealed that most (70%) of the dissociated bladder afferent neurons from control rats were capsaicin sensitive, with high-threshold long-duration action potentials that were not blocked by tetrodotoxin (TTX; 1 microM). These neurons exhibited membrane potential relaxations during voltage responses elicited by depolarizing current pulses and phasic firing during sustained membrane depolarization. After CYP treatment, a similar proportion (71%) of bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes. However, the neurons were significantly larger in size (diameter 29.6 +/- 1.0 micrometer vs 23.6 +/- 0.8 micrometer in controls). TTX-resistant bladder afferent neurons from CYP-treated rats exhibited lower thresholds for spike activation (-25.4 +/- 0.5 mV) than those from control rats (-21.4 +/- 0.9 mV) and did not exhibit membrane potential relaxation during depolarization. Seventy percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited tonic firing (average 12.3 +/- 1.4 spikes during a 500 msec depolarizing pulse) versus phasic firing (1.2 +/- 0.2 spikes) in normal bladder afferent neurons. Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent neurons mimicked the changes in firing properties after CYP treatment. The peak density of an A-type K+ current (IA) during depolarizations to 0 mV in TTX-resistant bladder afferent neurons from CYP-treated rats was significantly smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the inactivation curve of the IA current was displaced to more hyperpolarized levels by approximately 15 mV after CYP treatment. These data suggest that chronic inflammation induces somal hypertrophy and increases the excitability of C-fiber bladder afferent neurons by suppressing IA channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.

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Author and article information

Contributors

Frances M. Sladek: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 22 July 2014

Volume: 9

Issue: 7

Electronic Location Identifier: e102644

Affiliations

[1 ]Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

[2 ]Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

[3 ]Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

[4 ]Department of Urology, Centre for Urology Research Excellence, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, United States of America

University of California Riverside, United States of America

Author notes

* E-mail: chuang82@ 123456ms26.hinet.net

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: YC MBC JN. Performed the experiments: YC WL CH. Analyzed the data: JN YC NY PT BR. Contributed reagents/materials/analysis tools: YC MBC. Contributed to the writing of the manuscript: JN YC PT.

Article

Publisher ID: PONE-D-14-13841

DOI: 10.1371/journal.pone.0102644

PMC ID: 4106869

PubMed ID: 25050870

SO-VID: ed4dc1bb-67d1-4bc7-93df-d872b7acf1cb

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 28 March 2014

Date accepted : 19 June 2014

Page count

Pages: 8

Funding

This work is funded by the National Science council Taiwan 101-2314-B-182A-017 -MY3 101-2314-B-182A-017 -MY3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. Relevant data are included within the paper, Tables 1 through 6.

Functional and Molecular Characterization of Hyposensitive Underactive Bladder Tissue and Urine in Streptozotocin-Induced Diabetic Rat

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

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PLOS Climate

Most cited references 37

International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes.

Diabetic bladder dysfunction: current translational knowledge.

Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.

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