Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders

Abstract

The case is compelling for the involvement of nerve growth factor (NGF) in the pathogenesis of lower urinary tract disease, especially in conditions with altered neural function. Remodeling of the micturition pathways occurs following experimental bladder-outlet obstruction, denervation, spinal cord injury, cystitis, and diabetes mellitus. Clinically, NGF levels are elevated in the bladders of men with benign prostatic hyperplasia, women with interstitial cystitis and in patients with idiopathic overactive bladder. Blockade of NGF, using either an endogenous antibody or an antibody against the NGF receptor, prevents neural plasticity and bladder overactivity in experimental models of these conditions. The ability of NGF to trigger bladder overactivity might rely on altering the properties of sodium or potassium channels (or their expression) in bladder afferent fibers. Therapies based on altered NGF levels, or changes in channel properties in afferent nerves, represent an intriguing avenue of investigation for the management of detrusor overactivity or diabetic cystopathy.

Key Points

  • Urinary bladder urothelium and smooth muscle manufactures nerve growth factor (NGF)

  • NGF influences adult afferent and noradrenergic nerves supplying the bladder

  • In animal models, a rise in NGF protein triggers structural changes in bladder afferent nerves that lead to increased bladder activity and lowering of urine volume thresholds for micturition

  • In humans with obstructed bladders, or those with interstitial cystitis, tissue levels of NGF are elevated compared to controls

  • NGF can exert its effects through changes in afferent ion conductance

  • NGF blockade, Na+ channel antagonists or antisense deoxyoligonucleotides prevent or reduce bladder overactivity in animal models of obstruction or cystitis

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Basic organization of the human nerve growth factor gene.
Figure 2: Activation of tyrosine kinase A receptor by neurotrophins, such as nerve growth factor, is responsible for their biological activity including cell growth.
Figure 3: Proposed sequence of events leading to overactive bladder with urgency, frequency and possibly urge incontinence, following stimuli such as inflammation, urethral obstruction, spinal cord injury and partial denervation.

Similar content being viewed by others

References

  1. Levi-Montalcini R and Angeletti PU (1966) Second symposium on catecholamines. Modification of sympathetic function. Immunosympathectomy. Pharmacol Rev 18: 619–628

    CAS  PubMed  Google Scholar 

  2. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237: 1154–1162

    Article  CAS  Google Scholar 

  3. Johnson EM Jr et al. (1980) Dorsal root ganglion neurons are destroyed by exposure in utero to maternal antibody to nerve growth factor. Science 219: 916–918

    Article  Google Scholar 

  4. Dupont MC et al. (2001) Histological and neurotrophic changes triggered by varying models of bladder inflammation. J Urol 166: 1111–1118

    Article  CAS  Google Scholar 

  5. Tuttle JB et al. (1994) Neural input regulates tissue NGF and growth of the adult urinary bladder. J Auton Nerv Syst 49: 147–158

    Article  CAS  Google Scholar 

  6. Steers WD et al. (1991) Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. J Clin Invest 88: 1709–1715

    Article  CAS  Google Scholar 

  7. Fahnestock M (1991) Structure and biosynthesis of nerve growth factor. Curr Top Microbiol Immunol 165: 1–26

    CAS  PubMed  Google Scholar 

  8. Franke U et al. (1983) The human gene for the beta subunit of nerve growth factor is located on the proximal short arm of chromosome 1. Science 222: 1248–1251

    Article  Google Scholar 

  9. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci 4: 299–309

    Article  CAS  Google Scholar 

  10. Gotz R and Schartl M (1994) The conservation of neurotrophic factors during vertebrate evolution. Comp Biochem Physiol Pharmacol Toxicol Endocrinol 108: 1–10

    Article  CAS  Google Scholar 

  11. D'Mello SR and Heinrich G (1991) Structural and functional identification of regulatory regions and cis elements surrounding the nerve growth factor gene promoter. Brain Res Mol Brain Res 11: 255–264

    Article  CAS  Google Scholar 

  12. Colangelo AM et al. (1996) Correlation between increased AP-1NGF binding activity and induction of nerve growth factor transcription by multiple signal transduction pathways in C6-2B glioma cells. Brain Res Mol Brain Res 35: 1–10

    Article  CAS  Google Scholar 

  13. Hengerer B et al. (1990) Lesion induced increase in nerve growth factor mRNA is mediated by c-fos. Proc Natl Acad Sci USA 87: 3899–3903

    Article  CAS  Google Scholar 

  14. Sherer T et al. (1998) Mechanisms of increased NGF production in vascular smooth muscle of the spontaneously hypertensive rat. Exp Cell Res 241: 186–193

    Article  CAS  Google Scholar 

  15. Sherer T et al. (1998) Increased nerve growth factor mRNA stability may underlie elevated nerve growth factor secretion from hypertensive vascular smooth muscle cells. Brain Res Mol Brain Res 62: 167–174

    Article  CAS  Google Scholar 

  16. Patapoutian A and Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11: 272–280

    Article  CAS  Google Scholar 

  17. Chao MV (1994) The p75 neurotrophin receptor. J Neurobiol 25: 1373–1385

    Article  CAS  Google Scholar 

  18. Ibanez C (2002) Jekyll-Hyde neurotrophins: the story of pro-NGF. Trends Neurosci 25: 284–286

    Article  CAS  Google Scholar 

  19. Kaplan DR et al. (1991) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350: 158–160

    Article  CAS  Google Scholar 

  20. Kaplan DR and Miller FD (1997) Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 9: 213–221

    Article  CAS  Google Scholar 

  21. York RD et al. (2000) Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rapl. Mol Cell Biol 20: 8069–8083

    Article  CAS  Google Scholar 

  22. Hempstead BL and Salzer JL (2002) Neurobiology. A glial spin on neurotrophins. Science 298: 1184–1186

    Article  CAS  Google Scholar 

  23. Chuang YC et al. (2001) The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor. J Urol 165: 975–979

    Article  CAS  Google Scholar 

  24. Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14: 453–501

    Article  CAS  Google Scholar 

  25. Vizzard MA et al. (2000) Developmental expression of urinary bladder neurotrophic factor mRNA and protein in the neonatal rat. Brain Res Dev Brain Res 119: 217–224

    Article  CAS  Google Scholar 

  26. Steers W et al. (1996) Innervation and nerve growth factor in the early postnatal rat bladder. Soc Neurosci Abstr 22: 92

    Google Scholar 

  27. Harper S and Davies AM (1990) NGF mRNA expression in developing cutaneous epithelium related to innervation density. Development 110: 515–519

    CAS  PubMed  Google Scholar 

  28. Tuttle JB et al. (1994) NGF, bFGF and CNTF increase survival of major pelvic ganglion neurons cultured from the adult rat. Neurosci Lett 173: 94–98

    Article  CAS  Google Scholar 

  29. Clemow DB et al. (1997) Efferent and afferent neuronal hypertrophy associated with micturition pathways in the spontaneously hypertensive rat. Neurourol Urodynam 16: 293–303

    Article  CAS  Google Scholar 

  30. Clemow DB et al. (1998) Altered regulation of bladder nerve growth factor and neurally mediated hyperactive voiding. Am J Physiol 275: R1279–R1286

    CAS  PubMed  Google Scholar 

  31. Gosling JA et al. (1986) Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J Urol 136: 501–507

    Article  CAS  Google Scholar 

  32. Gabella G et al. (1992) Hypertrophy and reversal of hypertrophy in rat pelvic ganglion neurons. J Neurocytol 21: 649–657

    Article  CAS  Google Scholar 

  33. Benowitz LI and Perrone-Bizzozero NI (1991) The expression of GAP-43 in relation to neuronal growth and plasticity. When, where, how and why? Prog Brain Res 89: 69–84

    Article  CAS  Google Scholar 

  34. Sugaya K et al. (2002) Biochemical and morphological effects of bladder pumping on the urinary bladder in rats. Neurourol Urodyn 21: 511–515

    Article  Google Scholar 

  35. Persson K et al. (1995) Protein kinase C in cyclic stretch-induced nerve growth factor production by urinary tract smooth muscle cells. Am J Physiol 269: C1018–C1024

    Article  CAS  Google Scholar 

  36. Abrams PH (1985) Detrusor instability in bladder outlet obstruction. Neurourol Urodyn 4: 317–324

    Article  Google Scholar 

  37. Steers WD and de Groat WC (1988) Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol 140: 864–871

    Article  CAS  Google Scholar 

  38. Klausner A et al. (2004) Increased excitability of voltage-gated sodium channels in rat model of bladder outlet obstruction. J Urol 171: 353A

    Article  Google Scholar 

  39. Chai T et al. (1999) Persistently increased voiding frequency despite relief of bladder outlet obstruction. J Urol 161: 1689–1693

    Article  CAS  Google Scholar 

  40. Kim JC et al. (2004) Nerve growth factor and vanilloid receptor expression, and detrusor instability, after relieving bladder outlet obstruction in rats. BJU Int 94: 915–918

    Article  CAS  Google Scholar 

  41. Leffler A et al. (2002) GDNF and NGF reverse changes in repriming of TTX-sensitive Na+ currents following axotomy of dorsal root ganglion neurons. J Neurophysiol 88: 650–658

    Article  CAS  Google Scholar 

  42. Black JA et al. (2004) Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108: 237–247

    Article  CAS  Google Scholar 

  43. Yoshimura N and de Groat WC (1997) Plasticity of Na+ channels in afferent neurones innervating rat urinary bladder following spinal cord injury. J Physiol 503: 269–276

    Article  CAS  Google Scholar 

  44. Son HC et al. (2005) A novel Na channel blocker ICM I-136 reduces detrusor overactivity in the spontaneous hypertensive rat. In International Continence Society, 2005 Aug 2; Montreal

    Google Scholar 

  45. Berggren T et al. (1993) Effects of unilateral pelvic ganglionectomy on urinary bladder function in the male rat. Scand J Urol Nephrol 27: 181–194

    Article  CAS  Google Scholar 

  46. de Groat WC et al. (1990) Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 30 (Suppl): S71–S78

    Article  Google Scholar 

  47. Vizzard MA (2000) Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp Neurol 161: 273–284

    Article  CAS  Google Scholar 

  48. Seki S et al. (2002) Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreflexia in spinal cord injured rats. J Urol 168: 2269–2274

    Article  CAS  Google Scholar 

  49. Black JA et al. (2003) Tetrodotoxin-resistant sodium channels Na(v)1.8/SNS and Na(v)1.9/NaN in afferent neurons innervating urinary bladder in control and spinal cord injured rats. Brain Res 963: 132–138

    Article  CAS  Google Scholar 

  50. Giannantoni A et al. (2004) Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic detrusor overactivity: a prospective randomized study. J Urol 172: 240–243

    Article  CAS  Google Scholar 

  51. Lowe EM et al. (1997) Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol 79: 572–577

    Article  CAS  Google Scholar 

  52. Okragly AJ et al. (1999) Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients. J Urol 161: 438

    Article  CAS  Google Scholar 

  53. Bjorling DE et al. (2001) Intravesical Escherichia coli lipopolysaccharide stimulates an increase in bladder nerve growth factor. BJU Int 87: 697–702

    Article  CAS  Google Scholar 

  54. Dmitrieva N and McMahon SB (1996) Sensitisation of visceral afferents by nerve growth factor in the adult rat. Pain 66: 87–97

    Article  CAS  Google Scholar 

  55. Hu VY et al. (2005) Decrease in bladder overactivity with REN1820 in rats with cyclophosphamide induced cystitis. J Urol 173: 1016–1021

    Article  Google Scholar 

  56. Baykara M et al. 2003 Does interstitial cystitis urine include possible factors effecting the nociceptive system of the spinal cord? Urol Int 71: 66–72

    Article  Google Scholar 

  57. Lamb K et al. (2004) Increased nerve growth factor expression triggers bladder overactivity. J Pain 5: 150–156

    Article  CAS  Google Scholar 

  58. McMahon SB et al. (1994) Expression and coexpression of trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12: 1161–1171

    Article  CAS  Google Scholar 

  59. Lewin GR et al. (1992) On the role of nerve growth factor in the development of myelinated nociceptors. J Neurosci 12: 1896–1905

    Article  CAS  Google Scholar 

  60. Yoshimura N et al. (2001) The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain. J Neurosci 21: 8690–8696

    Article  CAS  Google Scholar 

  61. Yoshimura N et al. (2001) Suppression of the tetrodotoxin-resistant sodium channel (PN3/SNS): a possible new treatment for bladder pain. Urology 57 (Suppl 1): 116–117

    PubMed  Google Scholar 

  62. Stewart WF et al. (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20: 327–333

    CAS  PubMed  Google Scholar 

  63. Farquhar-Smith WP et al. (2002) Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors. Pain 97: 11–21

    Article  CAS  Google Scholar 

  64. Christmas TJ et al. (1990) Nerve fiber proliferation in interstitial cystitis. Virchows Arch A Pathol Anat Histopathol 416: 447–451

    Article  CAS  Google Scholar 

  65. Charlton RG et al. (1999) Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder. BJU Int 84: 953–966

    Article  CAS  Google Scholar 

  66. Giannantoni A et al. (2005) Botulinum-A toxin injections in the detrusor muscle reduce nerve growth factor bladder tissue levels in patients affected by neurogenic detrusor overactivity. J Urol 173: 330A

    Article  Google Scholar 

  67. Brown JS et al. (2005) Urologic outcomes of diabetes. Diabetes Care 28: 177–185

    Article  Google Scholar 

  68. Steinbacher BC Jr and Nadelhaft I (1998) Increased levels of nerve growth factor in the urinary bladder and hypertrophy of dorsal root ganglion neurons in the diabetic rat. Brain Res 782: 255

    Article  CAS  Google Scholar 

  69. Goins WF et al. (2001) Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: potential treatment for diabetic bladder dysfunction. J Urol 165: 1748–1754

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William D Steers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steers, W., Tuttle, J. Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. Nat Rev Urol 3, 101–110 (2006). https://doi.org/10.1038/ncpuro0408

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro0408

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing