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Mechanisms of Disease: involvement of the urothelium in bladder dysfunction

Nature Clinical Practice Urology volume 4, pages 46–54 (2007)Cite this article

Abstract

Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions and solutes, a number of novel properties have been recently attributed to urothelial cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e. the ability to express a number of sensor molecules or respond to thermal, mechanical and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests that urothelial cells could be targets for neurotransmitters released from bladder nerves or that chemicals released by urothelial cells could alter afferent nerve excitability. Taken together, these and other findings highlighted in this article suggest a sensory function for the urothelium. Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction.

Key Points

  • The urothelium, a specialized lining of the urinary tract, has historically been viewed as a passive barrier to ions and solutes

  • There is evidence that the urothelium responds to both physiological and chemical stimuli and can release a number of signaling molecules

  • Release of chemical mediators from urothelial cells indicates that these cells have specialized sensory and signaling properties that could allow reciprocal communication with neighboring urothelial cells, as well as afferent and efferent nerves or other cells (i.e. myofibroblasts and immune or inflammatory cells) within the bladder wall

  • Various types of transient receptor potential channels including TRPV1 are expressed in the urothelium as well as in bladder afferent nerves

  • Results from TRPV1-null mice demonstrate that TRPV1 receptors are essential for normal mechanically evoked purinergic signaling by the urothelium, and indicate that the function of these receptors extends beyond pain sensation to include participation in normal bladder function

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Figure 1: Hypothetical model that depicts possible interactions between bladder afferent and efferent nerves, urothelial cells, smooth muscle and myofibroblasts.
Figure 2: Expression of transient receptor potential cation channel subfamily V member 1 (TRPV1) in urothelial cells of the rat urinary bladder.

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References

  1. Apodaca G (2004) The uroepithelium: not just a passive barrier. Traffic 5: 117–128

    Article  CAS  Google Scholar 

  2. Lewis SA (2000) Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol Renal Physiol 278: F867–F874

    Article  CAS  Google Scholar 

  3. Wang E et al. (2003) Hydrostatic pressure-regulated ion transport in bladder uroepithelium. Am J Physiol Renal Physiol 285: F651–F663

    Article  CAS  Google Scholar 

  4. Tammela T et al. (1993) Urothelial permeability of the isolated whole bladder. Neurourol Urodyn 12: 39–47

    Article  CAS  Google Scholar 

  5. Romih R et al. (2005) Differentiation of epithelial cells in the urinary tract. Cell Tissue Res 320: 259–268

    Article  Google Scholar 

  6. Martin BF (1972) Cell replacement and differentiation in transitional epithelium: a histological and autoradiographic study of the guinea-pig bladder and ureter. J Anatomy 112: 433–455

    CAS  Google Scholar 

  7. Hicks M (1975) The mammalian urinary bladder: an accommodating organ. Biol Rev 50: 215–246

    Article  CAS  Google Scholar 

  8. Brady CM et al. (2004) Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int 93: 770–776

    Article  CAS  Google Scholar 

  9. Acharya P et al. (2004) Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium. Am J Physiol Renal Physiol 287: F305–F318

    Article  CAS  Google Scholar 

  10. Parsons CL et al. (1979) Antibacterial activity of bladder surface mucin duplicated by exogenous glycosaminoglycan (heparin). Infect Immun 24: 552–557

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lavelle J et al. (2002) Bladder permeability barrier: recovery from selective injury of surface epithelial cells. Am J Physiol Renal Physiol 283: F242–F253

    Article  CAS  Google Scholar 

  12. Bassuk JA et al. (2003) Induction of urothelial cell proliferation by fibroblast growth factor-7 in RAG1-deficient mice. Adv Exp Med Biol 539: 623–633

    PubMed  Google Scholar 

  13. de Boer WI et al. (1996) Functions of fibroblast and transforming growth factors in primary organ-like cultures of normal human urothelium. Lab Invest 75: 147–156

    CAS  PubMed  Google Scholar 

  14. Anderson G et al. (2003) Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301: 105–107

    Article  CAS  Google Scholar 

  15. Apodaca G et al. (2003) Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol 284: F966–F976

    Article  CAS  Google Scholar 

  16. Truschel ST et al. (2001) Involvement of nitric oxide (NO) in bladder afferent and urothelial abnormalities following chronic spinal cord injury [abstract #842.9]. Soc Neurosci Abstr Program

  17. Keay SK et al. (2004) An antiproliferative factor from interstitial cystitis patients is a Frizzled 8 protein-related sialoglycopeptide. Proc Natl Acad Sci USA 101: 11803–11808

    Article  CAS  Google Scholar 

  18. Conrads TP et al.: CKAP4/p63 is a receptor for the frizzled-8 protein-related antiproliferative factor from interstitial cystitis patients. J Biol Chem, in press

  19. Schilling J and Hultgren S (2002) Recent advances into the pathogenesis of recurrent urinary tract infections: the bladder as a reservoir for uropathogenic Escherichia coli. Int J Antimicrob Agents 19: 457–460

    Article  CAS  Google Scholar 

  20. Birder L et al. (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 98: 13396–13401

    Article  CAS  Google Scholar 

  21. Birder L et al. (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 5: 856–860

    Article  CAS  Google Scholar 

  22. Dickson A et al. (2006) Peptidergic sensory and parasympathetic fiber sprouting in the mucosa of the rat urinary bladder in a chronic model of cyclophosphamide-induced cystitis. Neuroscience 139: 671–685

    Article  CAS  Google Scholar 

  23. Jen PY et al. (1995) Immunohistochemical localization of neuromarkers and neuropeptides in human fetal and neonatal urinary bladder. Br J Pharmacol 75: 230–235

    CAS  Google Scholar 

  24. Kunze A et al. (2006) Quantitative immunohistochemical study of the innervation of the guinea-pig lower urinary tract. Br J Urol 98: 424–429

    Article  Google Scholar 

  25. Sui GP et al. (2002) Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 90: 118–129

    Article  CAS  Google Scholar 

  26. Wiseman OJ et al. (2002) The ultrastructure of bladder lamina propria nerves in healthy subjects and patients with detrusor hyperreflexia. J Urol 168: 2040–2045

    Article  Google Scholar 

  27. Brading AF and McCloskey KD (2005) Mechanisms of disease: specialized interstitial cells of the urinary tract—an assessment of current knowledge. Nat Clin Pract Urol 2: 546–554

    Article  Google Scholar 

  28. Birder L et al. (2002) Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 22: 8063–8070

    Article  CAS  Google Scholar 

  29. Birder L et al. (2003) Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. Am J Physiol Renal Physiol 285: F423–F429

    Article  CAS  Google Scholar 

  30. Burnstock G (2001) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22: 182–188

    Article  CAS  Google Scholar 

  31. Chess-Williams R (2002) Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 22: 133–145

    Article  CAS  Google Scholar 

  32. Chopra B et al. (2005) Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J Physiol 562: 859–871

    Article  CAS  Google Scholar 

  33. Ferguson DR et al. (1997) ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—a possible sensory mechanism? J Physiol 505: 503–511

    Article  CAS  Google Scholar 

  34. Beckel J et al. (2006) Expression of functional nicotinic acetylcholine receptors in rat bladder epithelial cells. Am J Physiol 290: F103–F110

    CAS  Google Scholar 

  35. Petruska JC and Mendell LM (2004) The many functions of nerve growth factor: multiple actions on nociceptors. Neurosci Lett 361: 168–171

    Article  CAS  Google Scholar 

  36. Wolf-Johnston AS et al. (2003) Increased NGF and TRPV1 expression in urinary bladder and sensory neurons from cats with feline interstitial cystitis [abstract 608.4]. Soc Neurosci Abstr Program

  37. Ossovskaya VS and Bunnett NW (2005) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84: 579–621

    Article  Google Scholar 

  38. Carattino MD et al. (2005) Mutations in the pore region modify epithelial sodium channel gating by shear stress. J Biol Chem 280: 4393–4401

    Article  CAS  Google Scholar 

  39. Kanai AJ et al. (2006) Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists. Am J Physiol Renal Physiol, in press

  40. Wang E et al. (2005) ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J Clin Invest 115: 2412–2422

    Article  CAS  Google Scholar 

  41. Cockayne DA et al. (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407: 1011–1015

    Article  CAS  Google Scholar 

  42. Brady CM et al. (2004) P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46: 247–253

    Article  CAS  Google Scholar 

  43. Sun Y et al. (2001) Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J Urol 166: 1951–1956

    Article  CAS  Google Scholar 

  44. Burnstock G (2006) Purinergic signaling. Br J Pharmacol 147 (Suppl 1): S172–S181

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Andersson KE and Hedlund P (2002) Pharmacologic perspective on the physiology of the lower urinary tract. Urology 60: 13–20

    Article  Google Scholar 

  46. Tominaga M et al. (2001) Potentiation of capsaicin receptor activation by metabotropic ATP receptors: a possible mechanism for ATP-evoked pain and hypersensitivity. Proc Natl Acad Sci USA 29: 820–825

    Google Scholar 

  47. Nickel JC (2003) Interstitial cystitis—an elusive clinical target? J Urol 170: 816–817

    Article  Google Scholar 

  48. Parsons CL et al. (1998) The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 159: 1862–1867

    Article  CAS  Google Scholar 

  49. Gillenwater JY and Wein AJ (1998) Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis, National Institutes of Health, Bethesda, Maryland, August 28–29, 1987. J Urol 140: 203–206

    Article  Google Scholar 

  50. Birder L et al. (2004) Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am J Physiol Renal Physiol 287: F1084–F1091

    Article  CAS  Google Scholar 

  51. Wellner MC and Isenberg G (1994) Stretch effects on whole-cell currents of guinea pig urinary bladder myocytes. J Physiol 480: 439–448

    Article  CAS  Google Scholar 

  52. Caterina MJ (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Ann Rev Neurosci 24: 602–607

    Article  Google Scholar 

  53. Caterina MJ et al. (1997) The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature 389: 816–824

    Article  CAS  Google Scholar 

  54. Maggi CA (1992) Therapeutic potential of capsaicin-like molecules: studies in animals and humans. Life Sci 51: 1777–1781

    Article  CAS  Google Scholar 

  55. Chancellor MB and de Groat WC (1999) Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J Urol 162: 3–11

    Article  CAS  Google Scholar 

  56. Staskin DR and MacDiarmid SA (2006) Using anticholinergics to treat overactive bladder: the issue of treatment tolerability. Am J Med 119: 9–15

    Article  Google Scholar 

  57. Pathak AS and Aboseif SR (2005) Overactive bladder: drug therapy versus nerve stimulation. Nat Clin Pract Urol 2: 310–311

    Article  Google Scholar 

  58. Abrams P et al. (2006) Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 148: 565–578

    Article  CAS  Google Scholar 

  59. Hegde SS (2006) Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 147 (Suppl 2): S80–S87

    Article  CAS  Google Scholar 

  60. Yoshida M et al. (2006) Non-neuronal cholinergic system in human bladder urothelium. Urology 67: 425–430

    Article  Google Scholar 

  61. Tiwari A and Naruganahalli KS (2006) Current and emerging investigational medical therapies for the treatment of overactive bladder. Expert Opin Investig Drugs 15: 1017–1037

    Article  CAS  Google Scholar 

  62. Chancellor MB (2005) Urgency, botulinum toxin and how botulinum toxin can help urgency. J Urol 174: 818

    Article  Google Scholar 

  63. Toft BR and Nordling J (2006) Recent developments of intravesical therapy of painful bladder syndrome/interstitial cystitis: a review. Current Opin Urol 16: 268–272

    Article  Google Scholar 

  64. Apostolidis A et al. (2006) Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol 49: 644–650

    Article  CAS  Google Scholar 

  65. Smith CP et al. (2005) Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int 47: 291–297

    Article  CAS  Google Scholar 

  66. Birder L et al. (1998) Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Physiol Renal Physiol 275: F226–F229

    Article  CAS  Google Scholar 

  67. Inoue T and Gabella G (1991) A vascular network closely linked to the epithelium of the urinary bladder of the rat. Cell Tissue Res 263: 137–143

    Article  CAS  Google Scholar 

  68. Toh KL and Ng CK (2006) Urodynamic studies in the evaluation of young men presenting with lower urinary tract symptoms. Int J Urol 13: 520–523

    Article  Google Scholar 

  69. Yassin A et al. (2006) Alpha-adrenoceptors are a common demoninator in the pathophysiology of erectile function and BPH/LUTS—implications for clinical practice. Andrologia 38: 1–12

    Article  CAS  Google Scholar 

  70. Chan Q et al. (2005) Function of the lower urinary tract in mice lacking alpha1D-adrenoceptor. J Urol 174: 370–374

    Article  Google Scholar 

  71. Ishihama H et al. (2006) Activation of alpha1D adrenergic receptors in the rat urothelium facilitates the micturition reflex. J Urol 175: 358–364

    Article  CAS  Google Scholar 

  72. Buffington CA et al. (2002) Norepinephrine content and adrenoceptor function in the bladder of cats with feline interstitial cystitis. J Urol 167: 1876–1880

    Article  CAS  Google Scholar 

  73. Birder L et al. (2005) Altered inducible nitric oxide synthase expression and nitric oxide production in urinary bladder from cats with feline interstitial cystitis. J Urol 173: 625–629

    Article  CAS  Google Scholar 

  74. Andersson KE and Persson K (1995) Nitric oxide synthase and the lower urinary tract: possible implications for physiology and pathophysiology. Scand J Urol Nephrol Suppl 175: 43–53

    CAS  PubMed  Google Scholar 

  75. Pandita RK et al. (2000) Intravesical oxyhemoglobin initiates bladder overactivity in conscious, normal rats. J Urol 164: 545–550

    Article  CAS  Google Scholar 

  76. de Groat WC et al. (1997) Modification of urinary bladder function after spinal cord injury. Adv Neurol 72: 347–364

    CAS  PubMed  Google Scholar 

  77. Ozawa H et al. (1999) Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol 162: 2211–2216

    Article  CAS  Google Scholar 

  78. Korkmaz A et al. (2005) Peroxynitrite may be involved in bladder damage caused by cyclophosphamide in rats. J Urol 173: 1793–1796

    Article  CAS  Google Scholar 

  79. Hosseini A et al. (2004) Nitric oxide as an objective marker for evaluation of treatment response in patients with classic interstitial cystitis. J Urol 172: 2261–2265

    Article  CAS  Google Scholar 

  80. Kolios G et al. (2004) Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology 113: 427–437

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grants to L Birder (RO1 DK54824 and RO1 DK57284).

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Authors and Affiliations

  1. LA Birder is an Assistant Professor in the Department of Medicine, Renal-Electrolyte Division, and also holds a secondary appointment in the Department of Pharmacology; WC de Groat is a Professor of Pharmacology in the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,

    Lori A Birder & William C de Groat

  2. WC de Groat is a Professor of Pharmacology in the Department of Pharmacology, WC de Groat is a Professor of Pharmacology in the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,

    Lori A Birder & William C de Groat

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Correspondence to Lori A Birder.

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Lori Birder has associations with the following companies: Hydra Biosciences Inc., Roche Palo Alto LLC, Dynogen Pharmaceuticals Inc., Pfizer Inc., and Omeros Corporation.

William C de Groat has associations with the following companies: Abbott Laboratories, Roche Palo Alto LLC, Eli Lilly and Company, Pfizer Inc., Novartis AG, Dynogen Pharmaceuticals Inc., Johnson & Johnson, Lilly ICOS LLC, Astellas Pharma Inc., Hydra Biosciences Inc., Boehringer Ingleheim, Allergan Inc. and Sanofi Aventis.

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Birder, L., de Groat, W. Mechanisms of Disease: involvement of the urothelium in bladder dysfunction. Nat Rev Urol 4, 46–54 (2007). https://doi.org/10.1038/ncpuro0672

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