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Published in: BMC Urology 1/2015

Open Access 01-12-2015 | Research article

Expression of brain derived-neurotrophic factor and granulocyte-colony stimulating factor in the urothelium: relation with voiding function

Authors: Seung Mo Yuk, Ju Hyun Shin, Ki Hak Song, Yong Gil Na, Jae Sung Lim, Chong Koo Sul

Published in: BMC Urology | Issue 1/2015

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Abstract

Background

We designed this experiment to elucidate the relationship between the expression of brain derived-neurotrophic factor (BDNF), the expression of granulocyte-colony stimulating factor (G-CSF), and the development of overactive bladder (OAB). In our previous study, the urothelium was observed to be more than a simple mechanosensory receptor and was found to be a potential therapeutic target for OAB. Moreover, neuregulin-1 and BDNF were found to be potential new biomarkers of OAB. Here, we investigated the relationship between changes in the voiding pattern and the expression of BDNF and G-CSF in the urothelium and evaluated the effects of 5-hydroxymethyl tolterodine (5-HMT) on rats with bladder outlet obstruction (BOO).

Methods

A total of 100 Sprague–Dawley rats were divided into the following groups: 20 control rats; 40 BOO rats; and 40 BOO rats administered 5-HMT (0.1 mg/kg). After BOO was induced for 4 weeks, the rats were assessed by cystometrography. The changes in BDNF and G-CSF expression were examined in both separated urothelial tissues and in cultured urothelial cells by reverse transcription polymerase chain reaction (RT-PCR).

Results

BOO rats showed increased non-voiding activity [NVA; (number/10 voidings)] and bladder weight and decreased micturition volume (MV), micturition interval (MI), and micturition time (MT) relative to the controls. Moreover, the 5-HMT administration rats showed decreased NVA and bladder weight and increased MV and MI in comparison to the BOO rats. BDNF and G-CSF expression was increased in BOO rats and decreased following 5-HMT administration. In this model, voiding dysfunction developed as a result of BOO. As a therapeutic agent for OAB, the administration of 5-HMT improved the voiding dysfunction.

Conclusions

BDNF and G-CSF might modulate voiding patterns through micturition pathways and might be involved only in the urothelium. Moreover, the expression of both genes in the urothelium might be related to voiding dysfunction in OAB patients. Thus, the urothelium has an important role in the manifestation of voiding symptoms.
Literature
1.
go back to reference Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167–78.CrossRefPubMed Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167–78.CrossRefPubMed
2.
go back to reference Kim JC, Yoo JS, Park EY, Hong SH, Il Seo S, Hwang TK. Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction. BJU Int. 2008;101(3):371–5.CrossRefPubMed Kim JC, Yoo JS, Park EY, Hong SH, Il Seo S, Hwang TK. Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction. BJU Int. 2008;101(3):371–5.CrossRefPubMed
3.
go back to reference Steers WD, De Groat WC. Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol. 1988;140(4):864–71.PubMed Steers WD, De Groat WC. Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol. 1988;140(4):864–71.PubMed
4.
go back to reference Fry CH, Sahai A, Vahabi B, Kanai AJ, Birder LA. What is the role for biomarkers for lower urinary tract disorders? ICI-RS 2013. Neurourol Urodyn. 2014;33(5):602–5.CrossRefPubMed Fry CH, Sahai A, Vahabi B, Kanai AJ, Birder LA. What is the role for biomarkers for lower urinary tract disorders? ICI-RS 2013. Neurourol Urodyn. 2014;33(5):602–5.CrossRefPubMed
5.
go back to reference Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F, et al. Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience. 2010;166(3):907–16.CrossRefPubMed Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F, et al. Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience. 2010;166(3):907–16.CrossRefPubMed
6.
go back to reference Michel MC. Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother. 2008;9(10):1787–96.CrossRefPubMed Michel MC. Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother. 2008;9(10):1787–96.CrossRefPubMed
7.
go back to reference Andersson KE. Storage and voiding symptoms: pathophysiologic aspects. Urology. 2003;62(5 Suppl 2):3–10.CrossRefPubMed Andersson KE. Storage and voiding symptoms: pathophysiologic aspects. Urology. 2003;62(5 Suppl 2):3–10.CrossRefPubMed
8.
go back to reference Fullhase C, Soler R, Gratzke C, Brodsky M, Christ GJ, Andersson KE. Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction. BJU Int. 2010;106(2):287–93.CrossRefPubMed Fullhase C, Soler R, Gratzke C, Brodsky M, Christ GJ, Andersson KE. Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction. BJU Int. 2010;106(2):287–93.CrossRefPubMed
9.
go back to reference Melman A, Tar M, Boczko J, Christ G, Leung AC, Zhao W, et al. Evaluation of two techniques of partial urethral obstruction in the male rat model of bladder outlet obstruction. Urology. 2005;66(5):1127–33.CrossRefPubMed Melman A, Tar M, Boczko J, Christ G, Leung AC, Zhao W, et al. Evaluation of two techniques of partial urethral obstruction in the male rat model of bladder outlet obstruction. Urology. 2005;66(5):1127–33.CrossRefPubMed
10.
go back to reference Kurzrock EA, Lieu DK, de Graffenried LA, Isseroff RR. Rat urothelium: improved techniques for serial cultivation, expansion, freezing and reconstitution onto acellular matrix. J Urol. 2005;173(1):281–5.CrossRefPubMed Kurzrock EA, Lieu DK, de Graffenried LA, Isseroff RR. Rat urothelium: improved techniques for serial cultivation, expansion, freezing and reconstitution onto acellular matrix. J Urol. 2005;173(1):281–5.CrossRefPubMed
11.
go back to reference Lluel P, Duquenne C, Martin D. Experimental bladder instability following bladder outlet obstruction in the female rat. J Urol. 1998;160(6 Pt 1):2253–7.CrossRefPubMed Lluel P, Duquenne C, Martin D. Experimental bladder instability following bladder outlet obstruction in the female rat. J Urol. 1998;160(6 Pt 1):2253–7.CrossRefPubMed
12.
go back to reference Lee T, Andersson KE, Streng T, Hedlund P. Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats–effects of bladder outlet obstruction and intravesical PGE2. NeurourolUrodyn. 2008;27(1):88–95. Lee T, Andersson KE, Streng T, Hedlund P. Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats–effects of bladder outlet obstruction and intravesical PGE2. NeurourolUrodyn. 2008;27(1):88–95.
13.
go back to reference Streng T, Hedlund P, Talo A, Andersson KE, Gillespie JI. Phasic non-micturition contractions in the bladder of the anaesthetized and awake rat. BJU Int. 2006;97(5):1094–101.CrossRefPubMed Streng T, Hedlund P, Talo A, Andersson KE, Gillespie JI. Phasic non-micturition contractions in the bladder of the anaesthetized and awake rat. BJU Int. 2006;97(5):1094–101.CrossRefPubMed
14.
go back to reference Gillespie JI. The autonomous bladder: a view of the origin of bladder overactivity and sensory urge. BJU Int. 2004;93(4):478–83.CrossRefPubMed Gillespie JI. The autonomous bladder: a view of the origin of bladder overactivity and sensory urge. BJU Int. 2004;93(4):478–83.CrossRefPubMed
15.
go back to reference Gillespie JI, van Koeveringe GA, de Wachter SG, de Vente J. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 2009;103(10):1324–33.CrossRefPubMed Gillespie JI, van Koeveringe GA, de Wachter SG, de Vente J. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 2009;103(10):1324–33.CrossRefPubMed
16.
go back to reference Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int. 2012;110(2 Pt 2):E132–42.CrossRefPubMed Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int. 2012;110(2 Pt 2):E132–42.CrossRefPubMed
17.
go back to reference Kaiho Y, Nishiguchi J, Kwon DD, Chancellor MB, Arai Y, Snyder PB, et al. The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction. BJU Int. 2008;101(5):615–20.CrossRefPubMed Kaiho Y, Nishiguchi J, Kwon DD, Chancellor MB, Arai Y, Snyder PB, et al. The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction. BJU Int. 2008;101(5):615–20.CrossRefPubMed
18.
go back to reference Yoshimura N. Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder. Prog Neurobiol. 1999;57(6):583–606.CrossRefPubMed Yoshimura N. Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder. Prog Neurobiol. 1999;57(6):583–606.CrossRefPubMed
19.
go back to reference McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263–84.CrossRefPubMed McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263–84.CrossRefPubMed
20.
go back to reference Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79(4):572–7.CrossRefPubMed Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79(4):572–7.CrossRefPubMed
21.
go back to reference Steers WD, Tuttle JB. Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. Nat Clin Pract Urol. 2006;3(2):101–10.CrossRefPubMed Steers WD, Tuttle JB. Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. Nat Clin Pract Urol. 2006;3(2):101–10.CrossRefPubMed
22.
go back to reference Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol. 2006;175(5):1773–6. discussion 1776.CrossRefPubMed Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol. 2006;175(5):1773–6. discussion 1776.CrossRefPubMed
23.
go back to reference Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20(4):709–26.CrossRefPubMed Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20(4):709–26.CrossRefPubMed
24.
go back to reference Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010;58(3):360–5.CrossRefPubMed Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010;58(3):360–5.CrossRefPubMed
25.
go back to reference Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005;115(8):2083–98.CrossRefPubMedPubMedCentral Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005;115(8):2083–98.CrossRefPubMedPubMedCentral
26.
go back to reference McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, et al. Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades. Oncotarget. 2012;3(9):954–87.CrossRefPubMedPubMedCentral McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, et al. Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades. Oncotarget. 2012;3(9):954–87.CrossRefPubMedPubMedCentral
27.
go back to reference Kawada H, Takizawa S, Takanashi T, Morita Y, Fujita J, Fukuda K, et al. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation. 2006;113(5):701–10.CrossRefPubMed Kawada H, Takizawa S, Takanashi T, Morita Y, Fujita J, Fukuda K, et al. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation. 2006;113(5):701–10.CrossRefPubMed
28.
go back to reference Liu F, Yao L, Yuan J, Liu H, Yang X, Qin W, et al. Protective effects of inosine on urinary bladder function in rats with partial bladder outlet obstruction. Urology. 2009;73(6):1417–22.CrossRefPubMed Liu F, Yao L, Yuan J, Liu H, Yang X, Qin W, et al. Protective effects of inosine on urinary bladder function in rats with partial bladder outlet obstruction. Urology. 2009;73(6):1417–22.CrossRefPubMed
29.
go back to reference Finney SM, Andersson KE, Gillespie JI, Stewart LH. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions? BJU Int. 2006;98(3):503–7.CrossRefPubMed Finney SM, Andersson KE, Gillespie JI, Stewart LH. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions? BJU Int. 2006;98(3):503–7.CrossRefPubMed
30.
go back to reference Bhide AA, Cartwright R, Khullar V, Digesu GA. Biomarkers in overactive bladder. Int Urogynecol J. 2013;24(7):1065–72.CrossRefPubMed Bhide AA, Cartwright R, Khullar V, Digesu GA. Biomarkers in overactive bladder. Int Urogynecol J. 2013;24(7):1065–72.CrossRefPubMed
31.
go back to reference Antunes-Lopes T, Carvalho-Barros S, Cruz CD, Cruz F, Martins-Silva C. Biomarkers in overactive bladder: a new objective and noninvasive tool? Adv Urol. 2011;2011:382431.CrossRefPubMedPubMedCentral Antunes-Lopes T, Carvalho-Barros S, Cruz CD, Cruz F, Martins-Silva C. Biomarkers in overactive bladder: a new objective and noninvasive tool? Adv Urol. 2011;2011:382431.CrossRefPubMedPubMedCentral
32.
go back to reference Wang LW, Han XM, Chen CH, Ma Y, Hai B. Urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. Int Urol Nephrol 2014. 2014;46(2):341–7.CrossRef Wang LW, Han XM, Chen CH, Ma Y, Hai B. Urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. Int Urol Nephrol 2014. 2014;46(2):341–7.CrossRef
33.
go back to reference Ghoniem G, Faruqui N, Elmissiry M, Mahdy A, Abdelwahab H, Oommen M, et al. Differential profile analysis of urinary cytokines in patients with overactive bladder. Int Urogynecol J. 2011;22(8):953–61.CrossRefPubMed Ghoniem G, Faruqui N, Elmissiry M, Mahdy A, Abdelwahab H, Oommen M, et al. Differential profile analysis of urinary cytokines in patients with overactive bladder. Int Urogynecol J. 2011;22(8):953–61.CrossRefPubMed
34.
go back to reference Zarghooni S, Wunsch J, Bodenbenner M, Bruggmann D, Grando SA, Schwantes U, et al. Expression of muscarinic and nicotinic acetylcholine receptors in the mouse urothelium. Life Sci. 2007;80(24–25):2308–13.CrossRefPubMed Zarghooni S, Wunsch J, Bodenbenner M, Bruggmann D, Grando SA, Schwantes U, et al. Expression of muscarinic and nicotinic acetylcholine receptors in the mouse urothelium. Life Sci. 2007;80(24–25):2308–13.CrossRefPubMed
35.
go back to reference Kullmann FA, Artim D, Beckel J, Barrick S, de Groat WC, Birder LA. Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat. Am J Physiol Renal Physiol. 2008;294(4):F971–81.CrossRefPubMedPubMedCentral Kullmann FA, Artim D, Beckel J, Barrick S, de Groat WC, Birder LA. Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat. Am J Physiol Renal Physiol. 2008;294(4):F971–81.CrossRefPubMedPubMedCentral
36.
go back to reference Ney P, Pandita RK, Newgreen DT, Breidenbach A, Stohr T, Andersson KE. Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU Int. 2008;101(8):1036–42.CrossRefPubMed Ney P, Pandita RK, Newgreen DT, Breidenbach A, Stohr T, Andersson KE. Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU Int. 2008;101(8):1036–42.CrossRefPubMed
Metadata
Title
Expression of brain derived-neurotrophic factor and granulocyte-colony stimulating factor in the urothelium: relation with voiding function
Authors
Seung Mo Yuk
Ju Hyun Shin
Ki Hak Song
Yong Gil Na
Jae Sung Lim
Chong Koo Sul
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Urology / Issue 1/2015
Electronic ISSN: 1471-2490
DOI
https://doi.org/10.1186/s12894-015-0036-3

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