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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
Similar content being viewed by others
References
Levi-Montalcini R and Angeletti PU (1966) Second symposium on catecholamines. Modification of sympathetic function. Immunosympathectomy. Pharmacol Rev 18: 619–628
Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237: 1154–1162
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
Dupont MC et al. (2001) Histological and neurotrophic changes triggered by varying models of bladder inflammation. J Urol 166: 1111–1118
Tuttle JB et al. (1994) Neural input regulates tissue NGF and growth of the adult urinary bladder. J Auton Nerv Syst 49: 147–158
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
Fahnestock M (1991) Structure and biosynthesis of nerve growth factor. Curr Top Microbiol Immunol 165: 1–26
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
Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci 4: 299–309
Gotz R and Schartl M (1994) The conservation of neurotrophic factors during vertebrate evolution. Comp Biochem Physiol Pharmacol Toxicol Endocrinol 108: 1–10
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
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
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
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
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
Patapoutian A and Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11: 272–280
Chao MV (1994) The p75 neurotrophin receptor. J Neurobiol 25: 1373–1385
Ibanez C (2002) Jekyll-Hyde neurotrophins: the story of pro-NGF. Trends Neurosci 25: 284–286
Kaplan DR et al. (1991) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350: 158–160
Kaplan DR and Miller FD (1997) Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 9: 213–221
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
Hempstead BL and Salzer JL (2002) Neurobiology. A glial spin on neurotrophins. Science 298: 1184–1186
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
Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14: 453–501
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
Steers W et al. (1996) Innervation and nerve growth factor in the early postnatal rat bladder. Soc Neurosci Abstr 22: 92
Harper S and Davies AM (1990) NGF mRNA expression in developing cutaneous epithelium related to innervation density. Development 110: 515–519
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
Clemow DB et al. (1997) Efferent and afferent neuronal hypertrophy associated with micturition pathways in the spontaneously hypertensive rat. Neurourol Urodynam 16: 293–303
Clemow DB et al. (1998) Altered regulation of bladder nerve growth factor and neurally mediated hyperactive voiding. Am J Physiol 275: R1279–R1286
Gosling JA et al. (1986) Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J Urol 136: 501–507
Gabella G et al. (1992) Hypertrophy and reversal of hypertrophy in rat pelvic ganglion neurons. J Neurocytol 21: 649–657
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
Sugaya K et al. (2002) Biochemical and morphological effects of bladder pumping on the urinary bladder in rats. Neurourol Urodyn 21: 511–515
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
Abrams PH (1985) Detrusor instability in bladder outlet obstruction. Neurourol Urodyn 4: 317–324
Steers WD and de Groat WC (1988) Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol 140: 864–871
Klausner A et al. (2004) Increased excitability of voltage-gated sodium channels in rat model of bladder outlet obstruction. J Urol 171: 353A
Chai T et al. (1999) Persistently increased voiding frequency despite relief of bladder outlet obstruction. J Urol 161: 1689–1693
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
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
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
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
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
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
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
Vizzard MA (2000) Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp Neurol 161: 273–284
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
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
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
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
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
Bjorling DE et al. (2001) Intravesical Escherichia coli lipopolysaccharide stimulates an increase in bladder nerve growth factor. BJU Int 87: 697–702
Dmitrieva N and McMahon SB (1996) Sensitisation of visceral afferents by nerve growth factor in the adult rat. Pain 66: 87–97
Hu VY et al. (2005) Decrease in bladder overactivity with REN1820 in rats with cyclophosphamide induced cystitis. J Urol 173: 1016–1021
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
Lamb K et al. (2004) Increased nerve growth factor expression triggers bladder overactivity. J Pain 5: 150–156
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
Lewin GR et al. (1992) On the role of nerve growth factor in the development of myelinated nociceptors. J Neurosci 12: 1896–1905
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
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
Stewart WF et al. (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20: 327–333
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
Christmas TJ et al. (1990) Nerve fiber proliferation in interstitial cystitis. Virchows Arch A Pathol Anat Histopathol 416: 447–451
Charlton RG et al. (1999) Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder. BJU Int 84: 953–966
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
Brown JS et al. (2005) Urologic outcomes of diabetes. Diabetes Care 28: 177–185
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
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
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpuro0408
This article is cited by
-
Role of Intravesical Ozone in the Management of BPS/Interstitial Cystitis
Current Bladder Dysfunction Reports (2023)
-
Managing Interstitial Cystitis/Bladder Pain Syndrome in Older Adults
Drugs & Aging (2021)
-
Diagnostic value of nerve growth factor in detrusor overactivity: a study on women with mixed urinary incontinence
International Urology and Nephrology (2021)
-
Association between overactive bladder and serum nerve growth factor concentrations in women with high-grade uterine prolapse
International Urogynecology Journal (2021)
-
Systemic Therapy for Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC): Systematic Review of Published Trials in the Last 5 Years
Current Bladder Dysfunction Reports (2020)