Top

BMC Urology

Published in:

Open Access 01-12-2013 | Research article

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

Authors: Hoon Jang, Dong Seok Han, Seung Mo Yuk

Published in: BMC Urology | Issue 1/2013

Abstract

Background

To determine whether neuregulin-1(NRG-1) is a potential new biomarker of overactive bladder (OAB) induced by partial urethral obstruction in a rat model of OAB and to evaluate the urothelium as a therapeutic target of OAB.

Methods

Female Sprague–Dawley rats were separated into three 20-animal groups: normal, OAB, and 5-hydroxymethyl tolterodine (5-HMT)-treated OAB. In the OAB and OAB + 5-HMT groups, the urethra of each animal was partially obstructed; the OAB + 5-HMT group received intravenous 5-HMT for 3 weeks. At the conclusion of the 5-HMT dosing, the rats in each group underwent cystometrography, and the bladders were histologically evaluated. The expression of brain derived-neurotrophic factor (BDNF) and NRG-1 were evaluated in the urothelium.

Results

Compared with the control group, the OAB group showed a markedly increased bladder weight and a significant decrease in the micturition interval and volume; rats in the OAB + 5-HMT group showed decreased bladder weights and an improved micturition interval and volume. BDNF and NRG-1 were expressed at significantly higher levels in the OAB group, and were significantly reduced in the OAB + 5-HMT group compared with the control group.

Conclusions

The study suggests that NRG-1 is a potential new biomarker of OAB; the urothelium might be a therapeutic target for OAB treatment.

Available only for authorised users

Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A: 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): 167-178.CrossRefPubMed

Chapple CR, Artibani W, Cardozo LD, Castro-Diaz D, Craggs M, Haab F, Khullar V, Versi E: The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. BJU Int. 2005, 95 (3): 335-340.CrossRefPubMed

Nixon A, Colman S, Sabounjian L, Sandage B, Schwiderski UE, Staskin DR, Zinner N: A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials. J Urol. 2005, 174 (2): 604-607.CrossRefPubMed

Starkman JS, Dmochowski RR: Urgency assessment in the evaluation of overactive bladder (OAB). Neurourol Urodyn. 2008, 27 (1): 13-21.CrossRefPubMed

Hashim H, Abrams P: Is the bladder a reliable witness for predicting detrusor overactivity?. J Urol. 2006, 175 (1): 191-194. discussion 194–195CrossRefPubMed

Bhide AA, Cartwright R, Khullar V, Digesu GA: Biomarkers in overactive bladder. Int Urogynecol J. 2013, 24 (7): 1065-1072.CrossRefPubMed

Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, et al: Identification of heregulin, a specific activator of p185erbB2. Science. 1992, 256 (5060): 1205-1210.CrossRefPubMed

Britsch S: The neuregulin-I/ErbB signaling system in development and disease. Adv Anat Embryol Cell Biol. 2007, 190: 1-65.CrossRefPubMed

Talmage DA: Mechanisms of neuregulin action. Novartis Found Symp. 2008, 289: 74-84. discussion 84–93CrossRefPubMedPubMedCentral

10.

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): 287-293.CrossRefPubMed

11.

Melman A, Tar M, Boczko J, Christ G, Leung AC, Zhao W, Russell RG: Evaluation of two techniques of partial urethral obstruction in the male rat model of bladder outlet obstruction. Urology. 2005, 66 (5): 1127-1133.CrossRefPubMed

12.

Parsons BA, Drake MJ: Animal models in overactive bladder research. Handb Exp Pharmacol. 2011, 202: 15-43.CrossRefPubMed

13.

Liu HT, Chancellor MB, Kuo HC: Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int. 2009, 103 (12): 1668-1672.CrossRefPubMed

14.

Salvatore S, Soligo M, Proietti F, Citterio S, Artibani W, Milani R: Overactive bladder syndrome: considerations in pharmacotherapy and new perspectives. Eur J Obstet Gynecol Reprod Biol. 2005, 120 (2): 129-133.CrossRefPubMed

15.

Andersson KE, Hedlund P: Pharmacologic perspective on the physiology of the lower urinary tract. Urology. 2002, 60 (5 Suppl 1): 13-20. discussion 20–11CrossRefPubMed

16.

Yoshimura N, Chancellor MB: Current and future pharmacological treatment for overactive bladder. J Urol. 2002, 168 (5): 1897-1913.CrossRefPubMed

17.

Andersson KE: Antimuscarinics for treatment of overactive bladder. Lancet Neurol. 2004, 3 (1): 46-53.CrossRefPubMed

18.

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): 1036-1042.CrossRefPubMed

19.

Apostolidis A, Dasgupta P, Fowler CJ: Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol. 2006, 49 (4): 644-650.CrossRefPubMed

20.

Birder LA, de Groat WC: Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat Clin Pract Urol. 2007, 4 (1): 46-54.CrossRefPubMedPubMedCentral

21.

Moore CK, Goldman HB: The bladder epithelium and overactive bladder: what we know. Curr Urol Rep. 2006, 7 (6): 447-449.CrossRefPubMed

22.

Yoshimura N: Lower urinary tract symptoms (LUTS) and bladder afferent activity. Neurourol Urodyn. 2007, 26 (6 Suppl): 908-913.CrossRefPubMed

23.

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

24.

Maisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD: Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics. 1991, 10 (3): 558-568.CrossRefPubMed

25.

Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW: Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci. 1999, 19 (12): 5138-5148.PubMed

26.

Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R: BDNF as a pain modulator. Prog Neurobiol. 2008, 85 (3): 297-317.CrossRefPubMed

27.

Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q, Priestley JV: Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci. 1997, 17 (21): 8476-8490.PubMed

28.

Hellard D, Brosenitsch T, Fritzsch B, Katz DM: Cranial sensory neuron development in the absence of brain-derived neurotrophic factor in BDNF/Bax double null mice. Dev Biol. 2004, 275 (1): 34-43.CrossRefPubMed

29.

Qiao LY, Vizzard MA: Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression and phosphorylation in rat micturition pathways. J Comp Neurol. 2002, 454 (2): 200-211.CrossRefPubMed

30.

Qiao L, Vizzard MA: Up-regulation of tyrosine kinase (Trka, Trkb) receptor expression and phosphorylation in lumbosacral dorsal root ganglia after chronic spinal cord (T8-T10) injury. J Comp Neurol. 2002, 449 (3): 217-230.CrossRefPubMed

31.

Qiao LY, Vizzard MA: Spinal cord injury-induced expression of TrkA, TrkB, phosphorylated CREB, and c-Jun in rat lumbosacral dorsal root ganglia. J Comp Neurol. 2005, 482 (2): 142-154.CrossRefPubMed

32.

Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F, Cruz CD: 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): 907-916.CrossRefPubMed

33.

Antunes-Lopes T, Pinto R, Carvalho-Barros S, Diniz P, Martins-Silva C, Duarte-Cruz C, Cruz F: Urinary levels of brain derived neurotrophic factor (bdnf) in women with overactive bladder (Oab) syndrome correlate with the severity of symptoms. Eur Urol Suppl. 2011, 10 (2): 277-278.CrossRef

34.

Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM, Cruz C, Cruz F, Dinis P: Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010, 58 (3): 360-365.CrossRefPubMed

35.

Orr-Urtreger A, Trakhtenbrot L, Ben-Levy R, Wen D, Rechavi G, Lonai P, Yarden Y: Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. Proc Natl Acad Sci USA. 1993, 90 (5): 1867-1871.CrossRefPubMedPubMedCentral

36.

Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, et al: Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993, 362 (6418): 312-318.CrossRefPubMed

37.

Wen D, Peles E, Cupples R, Suggs SV, Bacus SS, Luo Y, Trail G, Hu S, Silbiger SM, Levy RB, et al: Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992, 69 (3): 559-572.CrossRefPubMed

38.

Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD: ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993, 72 (5): 801-815.CrossRefPubMed

39.

Steinthorsdottir V, Stefansson H, Ghosh S, Birgisdottir B, Bjornsdottir S, Fasquel AC, Olafsson O, Stefansson K, Gulcher JR: Multiple novel transcription initiation sites for NRG1. Gene. 2004, 342 (1): 97-105.CrossRefPubMed

40.

Bindels EM, van der Kwast TH, Izadifar V, Chopin DK, de Boer WI: Functions of epidermal growth factor-like growth factors during human urothelial reepithelialization in vitro and the role of erbB2. Neurol Res. 2002, 30 (4): 240-247.

41.

Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW: Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation. 2004, 109 (3): 324-326.CrossRefPubMed

42.

Okoshi K, Nakayama M, Yan X, Okoshi MP, Schuldt AJ, Marchionni MA, Lorell BH: Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation. 2004, 110 (6): 713-717.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2490/13/54/prepub

Title: Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?
Authors: Hoon Jang
Dong Seok Han
Seung Mo Yuk
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: BMC Urology / Issue 1/2013
Electronic ISSN: 1471-2490
DOI: https://doi.org/10.1186/1471-2490-13-54

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2013

Chromophobe renal cell carcinoma with concomitant sarcomatoid transformation and osseous metaplasia: a case report

Transurethral marking incision of the bladder neck: a helpful technique in robot-assisted laparoscopic radical prostatectomy involving post-transurethral resection of the prostate and cancers protruding into the bladder neck

Sequential compression devices in postoperative urologic patients: an observational trial and survey study on the influence of patient and hospital factors on compliance

Relationships between perioperative physical activity and urinary incontinence after radical prostatectomy: an observational study

Pheochromocytoma of the urinary bladder: a systematic review of the contemporary literature

Radiosensitization in prostate cancer: mechanisms and targets