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Sensor and Transducer Function of the Urothelium

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Neurourology

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Abstract

The urothelium, the epithelial layer of bladder mucosa, has the classic barrier function of preventing harmful urinary constituents from leaking into the underlying submucosal structures and smooth muscle. In recent years, this epithelial layer has been recognised as a new sensory structure that responds to bladder distension as well as pathological stimuli. This has changed our view on bladder sensory mechanisms and generated intense interest in its role in pathophysiology underlying many bladder disorders.

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References

  1. Martin BF. Cell replacement and differentiation in transitional epithelium: a histological and autoradiographic study of the guinea-pig bladder and ureter. J Anat. 1972;112:433–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu XR, Kong XP, Pellicer A, Kreibich G, Sun TT. Uroplakins in urothelial biology, function, and disease. Kidney Int. 2009;75:1153–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zeidel ML. Low permeabilities of apical membranes of barrier epithelia: what makes watertight membranes watertight? Am J Phys. 1996;271:243–5.

    Google Scholar 

  4. Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML. Permeability properties of the intact mammalian bladder epithelium. Am J Phys. 1996;271:886–94.

    Google Scholar 

  5. Kikeri D, Sun A, Zeidel ML, Hebert SC. Cell membranes impermeable to NH3. Nature. 1989;339:478–80.

    Article  CAS  PubMed  Google Scholar 

  6. Hicks RM. The permeability of rat transitional epithelium. Kertinization and the barrier to water. J Cell Biol. 1966;28:21–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hicks RM, Ketterer B, Warren RC. The ultrastructure and chemistry of the luminal plasma membrane of the mammalian urinary bladder: a structure with low permeability to water and ions. Philos Trans R Soc Lond Ser B Biol Sci. 1974;268:23–38.

    Article  CAS  Google Scholar 

  8. Clausen C, Lewis SA, Diamond JM. Impedance analysis of a tight epithelium using a distributed resistance model. Biophys J. 1979;26:291–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peter S. The junctional connections between the cells of the urinary bladder in the rat. Cell Tissue Res. 1978;187:439–48.

    Article  CAS  PubMed  Google Scholar 

  10. Lavelle JP, Apodaca G, Meyers SA, Ruiz WG, Zeidel ML. Disruption of guinea pig urinary bladder permeability barrier in noninfectious cystitis. Am J Phys. 1998;274:205–14.

    Google Scholar 

  11. Keay S, Warren JW, Zhang CO, Tu LM, Gordon DA, Whitmore KE. Antiproliferative activity is present in bladder but not renal pelvic urine from interstitial cystitis patients. J Urol. 1999;162:1487–9.

    Article  CAS  PubMed  Google Scholar 

  12. Keay S, Zhang CO, Chai T, Warren J, Koch K, Grkovic D, et al. Antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology. 2004;63:22–6.

    Article  PubMed  Google Scholar 

  13. Birder LA, Wolf-Johnston A, Buffington CA, Roppolo JR, de Groat WC, Kanai AJ. Altered inducible nitric oxide synthase expression and nitric oxide production in the bladder of cats with feline interstitial cystitis. J Urol. 2005;173:625–9.

    Article  CAS  PubMed  Google Scholar 

  14. Veranic P, Jezernik K. The response of junctional complexes to induced desquamation in mouse bladder urothelium. Biol Cell. 2000;92:105–13.

    Article  CAS  PubMed  Google Scholar 

  15. Hanna-Mitchell AT, Wolf-Johnston A, Roppolo JR, Buffington TC, Birder LA. Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells. J Endocrinol. 2014;222:113–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Veranic P, Jezernik K. Succession of events in desquamation of superficial urothelial cells as a response to stress induced by prolonged constant illumination. Tissue Cell. 2001;33:280–5.

    Article  CAS  PubMed  Google Scholar 

  17. Shie JH, Liu HT, Kuo HC. Increased cell apoptosis of urothelium mediated by inflammation in interstitial cystitis/painful bladder syndrome. Urology. 2012;79:484–13.

    PubMed  Google Scholar 

  18. Apodaca G, Kiss S, Ruiz W, Meyers S, Zeidel M, Birder L. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol. 2003;284:966–76.

    Article  Google Scholar 

  19. Ferguson DR, Kennedy I, Burton TJ. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes--a possible sensory mechanism? J Physiol. 1997;505:503–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rong W, Spyer KM, Burnstock G. Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder. J Physiol. 2002;541:591–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407:1011–5.

    Article  CAS  PubMed  Google Scholar 

  22. Vlaskovska M, Kasakov L, Rong W, Bodin P, Bardini M, Cockayne DA, et al. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci. 2001;21:5670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gabella G, Davis C. Distribution of afferent axons in the bladder of rats. J Neurocytol. 1998;27:141–55.

    Article  CAS  PubMed  Google Scholar 

  24. Wakabayashi Y, Tomoyoshi T, Fujimiya M, Arai R, Maeda T. Substance P-containing axon terminals in the mucosa of the human urinary bladder: pre-embedding immunohistochemistry using cryostat sections for electron microscopy. Histochemistry. 1993;100:401–7.

    Article  CAS  PubMed  Google Scholar 

  25. Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedeberg's Arch Pharmacol. 2006;373:287–99.

    Article  CAS  Google Scholar 

  26. Birder LA, Kanai AJ, de Groat WC, Kiss S, Nealen ML, Burke NE, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A. 2001;98:13396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Davidson RA, McCloskey KD. Morphology and localization of interstitial cells in the guinea pig bladder: structural relationships with smooth muscle and neurons. J Urol. 2005;173:1385–90.

    Article  PubMed  Google Scholar 

  28. Drake MJ, Fry CH, Eyden B. Structural characterization of myofibroblasts in the bladder. BJU Int. 2006;97:29–32.

    Article  PubMed  Google Scholar 

  29. Lagou M, De Vente J, Kirkwood TB, Hedlund P, Andersson KE, Gillespie JI, et al. Location of interstitial cells and neurotransmitters in the mouse bladder. BJU Int. 2006;97:1332–7.

    Article  CAS  PubMed  Google Scholar 

  30. Gillespie JI, Markerink-VAN IM, De Vente J. Interstitial cells and cholinergic signalling in the outer muscle layers of the guinea-pig bladder. BJU Int. 2006;97:379–85.

    Article  CAS  PubMed  Google Scholar 

  31. Smet PJ, Jonavicius J, Marshall VR, De Vente J. Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience. 1996;71:337–48.

    Article  CAS  PubMed  Google Scholar 

  32. Sui GP, Rothery S, Dupont E, Fry CH, Severs NJ. Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int. 2002;90:118–29.

    Article  CAS  PubMed  Google Scholar 

  33. McCloskey KD, Gurney AM. Kit positive cells in the guinea pig bladder. J Urol. 2002;168:832–6.

    Article  PubMed  Google Scholar 

  34. Wu C, Sui GP, Fry CH. Purinergic regulation of guinea pig suburothelial myofibroblasts. J Physiol. 2004;559:231–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sui GP, Wu C, Fry CH. Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol. 2004;171:938–43.

    Article  CAS  PubMed  Google Scholar 

  36. McCloskey KD. Characterization of outward currents in interstitial cells from the guinea pig bladder. J Urol. 2005;173:296–301.

    Article  CAS  PubMed  Google Scholar 

  37. McCloskey KD. Calcium currents in interstitial cells from the guinea-pig bladder. BJU Int. 2006;97:1338–43.

    Article  CAS  PubMed  Google Scholar 

  38. Wiseman OJ, Fowler CJ, Landon DN. The role of the human bladder lamina propria myofibroblast. BJU Int. 2003;91:89–93.

    Article  CAS  PubMed  Google Scholar 

  39. Gillespie JI, Markerink-VAN IM, De Vente J. cGMP-generating cells in the bladder wall: identification of distinct networks of interstitial cells. BJU Int. 2004;94:1114–24.

    Article  PubMed  Google Scholar 

  40. Gillespie JI, Markerink-van Ittersum M, De Vente J. Endogenous nitric oxide/cGMP signalling in the guinea pig bladder: evidence for distinct populations of sub-urothelial interstitial cells. Cell Tissue Res. 2006;325:325–32.

    Article  CAS  PubMed  Google Scholar 

  41. Wiseman OJ, Brady CM, Hussain IF, Dasgupta P, Watt H, Fowler CJ, et al. The ultrastructure of bladder lamina propria nerves in healthy subjects and patients with detrusor hyperreflexia. J Urol. 2002;168:2040–5.

    Article  PubMed  Google Scholar 

  42. Sui GP, Wu C, Fry CH. Characterization of the purinergic receptor subtype on guinea-pig suburothelial myofibroblasts. BJU Int. 2006;97:1327–31.

    Article  CAS  PubMed  Google Scholar 

  43. Ost D, Roskams T, Van Der AF, De Ridder D. Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers. J Urol. 2002;168:293–7.

    Article  PubMed  Google Scholar 

  44. Sui GP, Wu C, Roosen A, Ikeda Y, Kanai AJ, Fry CH. Modulation of bladder myofibroblast activity: implications for bladder function. Am J Physiol Renal Physiol. 2008;295:688–97.

    Article  CAS  Google Scholar 

  45. Wu C, Gui GP, Fry CH. Intracellular Ca(2+) regulation and electrophysiolgical properties of bladder urothelium subjected to stretch and exogenous agonists. Cell Calcium. 2011;49:395–9.

    Article  CAS  PubMed  Google Scholar 

  46. Birder LA, Ruan HZ, Chopra B, Xiang Z, Barrick S, Buffington CA, et al. Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am J Physiol Renal Physiol. 2004;287:1084–91.

    Article  CAS  Google Scholar 

  47. Wang EC, Lee JM, Ruiz WG, Balestreire EM, von Bodungen M, Barrick S, et al. ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J Clin Invest. 2005;115:2412–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Andrade EL, Ferreira J, Andre E, Calixto JB. Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder. Biochem Pharmacol. 2006;72:104–14.

    Article  CAS  PubMed  Google Scholar 

  49. Stein RJ, Santos S, Nagatomi J, Hayashi Y, Minnery BS, Xavier M, et al. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J Urol. 2004;172:1175–8.

    Article  CAS  PubMed  Google Scholar 

  50. Birder LA, Nealen ML, Kiss S, de Groat WC, Caterina MJ, Wang E, et al. Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci. 2002;22:8063–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chopra B, Barrick SR, Meyers S, Beckel JM, Zeidel ML, Ford AP, et al. Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J Physiol. 2005;562:859–71.

    Article  CAS  PubMed  Google Scholar 

  52. Wang X, Momota Y, Yanase H, Narumiya S, Maruyama T, Kawatani M. Urothelium EP1 receptor facilitates the micturition reflex in mice. Biomed Res. 2008;29:105–11.

    Article  PubMed  Google Scholar 

  53. Yu W, Zacharia LC, Jackson EK, Apodaca G. Adenosine receptor expression and function in bladder uroepithelium. Am J Physiol Cell Physiol. 2006;291:254–65.

    Article  CAS  Google Scholar 

  54. Makela S, Strauss L, Kuiper G, Valve E, Salmi S, Santti R, et al. Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract. Mol Cell Endocrinol. 2000;170:219–29.

    Article  CAS  PubMed  Google Scholar 

  55. Du S, Araki I, Mikami Y, Zakoji H, Beppu M, Yoshiyama M, et al. Amiloride-sensitive ion channels in urinary bladder epithelium involved in mechanosensory transduction by modulating stretch-evoked adenosine triphosphate release. Urology. 2007;69:590–5.

    Article  PubMed  Google Scholar 

  56. Birder LA, Wolf-Johnston A, Griffiths D, Resnick NM. Role of urothelial nerve growth factor in human bladder function. Neurourol Urodyn. 2007;26:405–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Birder LA. More than just a barrier: urothelium as a drug target for urinary bladder pain. Am J Physiol Renal Physiol. 2005;289:489–95.

    Article  CAS  Google Scholar 

  58. Birder LA, Apodaca G, de Groat WC, Kanai AJ. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Phys. 1998;275:226–9.

    Google Scholar 

  59. Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, Sugiyama Y, et al. Non-neuronal cholinergic system in human bladder urothelium. Urology. 2006;67:425–30.

    Article  PubMed  Google Scholar 

  60. Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci. 2002;5:856–60.

    Article  CAS  PubMed  Google Scholar 

  61. Sui G, Fry CH, Montgomery B, Roberts M, Wu R, Wu C. Purinergic and muscarinic modulation of ATP release from the urothelium and its paracrine actions. Am J Physiol Renal Physiol. 2014;306:286–98.

    Article  CAS  Google Scholar 

  62. Wu C, Sui G, Archer SN, Sassone-Corsi P, Aitken K, Bagli D, et al. Local receptors as novel regulators for peripheral clock expression. FASEB J. 2014;28:4610–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ma F, Kouzoukas DE, Meyer-Siegler KL, Westlund KN, Hunt DE, Vera PL. Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4. BMC Physiol. 2017;17:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Warburton AL, Santer RM. Sympathetic and sensory innervation of the urinary tract in young adult and aged rats: a semi-quantitative histochemical and immunohistochemical study. Histochem J. 1994;26:127–33.

    Article  CAS  PubMed  Google Scholar 

  65. Jacob J, Ludgate CM, Forde J, Tulloch WS. Recent observations on the ultrastructure of human urothelium. 1. Normal bladder of elderly subjects. Cell Tissue Res. 1978;193:543–60.

    Article  CAS  PubMed  Google Scholar 

  66. Phillips JI. Inflammatory plasma cell infiltration of the urinary bladder in the aging C57BL/Icrfa(t) mouse. Investig Urol. 1981;19:75–8.

    CAS  Google Scholar 

  67. Yoshida M, Masunaga K, Satoji Y, Maeda Y, Nagata T, Inadome A. Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in urothelium and its clinical significance. J Pharmacol Sci. 2008;106:193–8.

    Article  CAS  PubMed  Google Scholar 

  68. Yoshida M, Miyamae K, Iwashita H, Otani M, Inadome A. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology. 2004;63:17–23.

    Article  PubMed  Google Scholar 

  69. Montalbetti N, Rued AC, Taiclet SN, Birder LA, Kullmann FA, Carattino MD. Urothelial tight junction barrier dysfunction sensitizes bladder afferents. eNeuro. 2017; https://doi.org/10.1523/ENEURO.0381-16.2017.

  70. Birder LA, de Groat WC. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat Clin Pract Urol. 2007;4:46–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kumar V, Chapple CR, Surprenant AM, Chess-Williams R. Enhanced adenosine triphosphate release from the urothelium of patients with painful bladder syndrome: a possible pathophysiological explanation. J Urol. 2007;178:1533–6.

    Article  CAS  PubMed  Google Scholar 

  72. Sun Y, Chai TC. Augmented extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis. Am J Physiol Cell Physiol. 2006;290:27–34.

    Article  CAS  Google Scholar 

  73. Birder LA, Barrick SR, Roppolo JR, Kanai AJ, de Groat WC, Kiss S, et al. Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. Am J Physiol Renal Physiol. 2003;285:423–9.

    Article  Google Scholar 

  74. Mansfield KJ, Liu L, Moore KH, Vaux KJ, Millard RJ, Burcher E. Molecular characterization of M2 and M3 muscarinic receptor expression in bladder from women with refractory idiopathic detrusor overactivity. BJU Int. 2007;99:1433–8.

    Article  CAS  PubMed  Google Scholar 

  75. Kumar V, Chapple CR, Rosario D, Tophill PR, Chess-Williams R. In vitro release of adenosine triphosphate from the urothelium of human bladders with detrusor overactivity, both neurogenic and idiopathic. Eur Urol. 2010;57:1087–92.

    Article  CAS  PubMed  Google Scholar 

  76. Datta SN, Roosen A, Pullen A, Popat R, Rosenbaum TP, Elneil S, et al. Immunohistochemical expression of muscarinic receptors in the urothelium and suburothelium of neurogenic and idiopathic overactive human bladders, and changes with botulinum neurotoxin administration. J Urol. 2010;184:2578–85.

    Article  CAS  PubMed  Google Scholar 

  77. Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, et al. P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol. 2004;46:247–53.

    Article  CAS  PubMed  Google Scholar 

  78. Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, et al. 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. 2004;93:770–6.

    Article  CAS  PubMed  Google Scholar 

  79. Roosen A, Datta SN, Chowdhury RA, Patel PM, Kalsi V, Elneil S, et al. Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin type A treatment. Eur Urol. 2009;55:1440–8.

    Article  CAS  PubMed  Google Scholar 

  80. Kim JC, Yoo JS, Park EY, Hong SH, Seo SI, Hwang TK. Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction. BJU Int. 2008;101:371–5.

    Article  CAS  PubMed  Google Scholar 

  81. Ikeda Y, Kanai A. Urotheliogenic modulation of intrinsic activity in spinal cord-transected rat bladders: role of mucosal muscarinic receptors. Am J Physiol Renal Physiol. 2008;295:454–61.

    Article  CAS  Google Scholar 

  82. Contreras-Sanz A, Krska L, Balachandran AA, Curtiss NL, Khasriya R, Kelley S, et al. Altered urothelial ATP signaling in a major subset of human overactive bladder patients with pyuria. Am J Physiol Renal Physiol. 2016;311:805–16.

    Article  CAS  Google Scholar 

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Acknowledgement

The author acknowledges the support from Biotechnology and Biological Sciences Research Council (BBSRC) (BB/P004695/1) and National Institute of Aging (NIA, 1R01AG049321-01A1).

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Authors and Affiliations

  1. Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK

    Changhao Wu

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Correspondence to Changhao Wu .

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  1. Department of Urology, China Rehabiliation Research Center Capital Medical University, Beijing, China

    Limin Liao

  2. Department of Urology, University Hospital, Innsbruck, Austria

    Helmut Madersbacher

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Wu, C. (2019). Sensor and Transducer Function of the Urothelium. In: Liao, L., Madersbacher, H. (eds) Neurourology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7509-0_2

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