Current Urology Reports

, Volume 7, Issue 6, pp 440–446 | Cite as

Dysfunction of bladder urothelium and bladder urothelial cells in interstitial cystitis

  • Emmanuel Graham
  • Toby C. Chai


The human bladder urothelium (BU) and bladder urothelial cells (BUCs) play an important role in the normal functioning of bladder including bladder storage. Current evidence in interstitial cystitis (IC) supports multiple abnormalities in bladder urothelial physiology. These data have come primarily from human studies. The discovery of a novel protein termed the antiproliferative factor (APF) uniquely expressed by IC BUCs is extremely important. APF induces increased permeability of normal BUCs grown in culture. Furthermore, APF regulates expression of other cytokines, including upregulating heparin-binding epidermal growth factor-like growth factor and downregulating epidermal growth factor by BUCs. These cytokine abnormalities were also related to increases in purinergic (adenosine triphosphate) signaling, which could mediate increased bladder sensation. Recent studies of uroplakins, which are specialized proteins expressed only in the apical urothelial cells, suggest that uroplakins play a role in the barrier function of the BU. It is also conceivable that alterations in uroplakins may result in bladder symptoms related to increased permeability or decreased protective function. As the body of knowledge about BU and BUC function increases, novel therapies targeting urothelial cells should become clinically feasible.


Interstitial Cystitis Urothelial Cell Bladder Urothelium Pentosan Polysulfate Interstitial Cystitis Patient 
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References and Recommended Reading

  1. 1.
    Trifillis AL, Cui X, Jacobs S, Warren JW: Culture of bladder epithelium from cystoscopic biopsies of patients with interstitial cystitis. J Urol 1995, 153:243–248.PubMedCrossRefGoogle Scholar
  2. 2.
    Acharya P, Beckel J, Ruiz WG, et al.: Distribution of tight junction proteins ZO-1, Occludin, and Claudin-4, -8, and - 12 in bladder epithelium. Am J Physiol Renal Physiol 2004, 287:F305-F318.PubMedCrossRefGoogle Scholar
  3. 3.
    Sun TT, Zhao H, Provet J, et al.: Formation of asymmetric unit membrane during urothelial differentiation. Mol Biol Rep 1996, 23:3–11.PubMedCrossRefGoogle Scholar
  4. 4.
    Kachar B, Liang F, Lins U, et al.: Three-dimensional analysis of the 16 nm urothelial plaque particle: luminal surface exposure, preferential head-to-head interaction, and hinge formation. J Mol Biol 1999, 285:595–608.PubMedCrossRefGoogle Scholar
  5. 5.
    Hu P, Deng FM, Liang FX, et al.: Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux. J Cell Biol 2000, 151:961–972.PubMedCrossRefGoogle Scholar
  6. 6.
    Hu P, Meyers S, Liang Fx, et al.: Role of membrane proteins in permeability barrier function: uroplakin ablation elevates urothelial permeability. Am J Physiol Renal Physiol 2002, 283:F1200-F1207.PubMedGoogle Scholar
  7. 7.
    Stahlschmidt J, Varley CL, Toogood G, et al.: Urothelial differentiation in chronically urine-deprived bladders of patients with end-stage renal disease. Kidney Int 2005, 68:1032–1040.PubMedCrossRefGoogle Scholar
  8. 8.
    Romih R, Jezernik K, Masera A: Uroplakins and cytokeratins in the regenerating rat urothelium after sodium saccharin treatment. Histochem Cell Biol 1998, 109:263–269.PubMedCrossRefGoogle Scholar
  9. 9.
    Parsons CL, Greenspan C, Mulholland SG: The primary antibacterial defense mechanism of the bladder. Invest Urol 1975, 13:72–78.PubMedCrossRefGoogle Scholar
  10. 10.
    Parsons CL, Stauffer C, Schmidt JD: Bladder-surface glycosaminoglycans: an efficient mechanism of environmental adaptation. Science 1980, 208:605–607.PubMedCrossRefGoogle Scholar
  11. 11.
    Hurst RE, Roy JB, Min KW, et al.: A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology 1996, 48:817–821.PubMedCrossRefGoogle Scholar
  12. 12.
    Wu XR, Sun TT, Medina JJ: In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc Natl Acad Sci U S A 1996, 93:9630–9635.PubMedCrossRefGoogle Scholar
  13. 13.
    Xie B, Zhou G, Chan SY, et al.: Distinct glycan structures of uroplakins Ia and Ib: structural basis for the selective binding of FimH adhesin to uroplakin Ia. J Biol Chem 2006, 281:14644–14653.PubMedCrossRefGoogle Scholar
  14. 14.
    Mulholland SG, Hanno P, Parsons CL, et al.: Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990, 35:552–558.PubMedCrossRefGoogle Scholar
  15. 15.
    Hwang P, Auclair B, Beechinor D, et al.: Efficacy of pentosan polysulfate in the treatment of interstitial cystitis: a meta-analysis. Urology 1997, 50:39–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Sant GR, Propert KJ, Hanno PM, et al.: Interstitial Cystitis Clinical Trials Group. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 2003, 170:810–815.PubMedCrossRefGoogle Scholar
  17. 17.
    Apodaca G: Modulation of membrane traffic by mechanical stimuli. Am J Physiol Renal Physiol 2002, 282:F179-F190.PubMedGoogle Scholar
  18. 18.
    Truschel ST, Wang E, Ruiz WG, et al.: Stretch-regulated exocytosis/endocytosis in bladder umbrella cells. Mol Biol Cell 2002, 13:830–846.PubMedCrossRefGoogle Scholar
  19. 19.
    Birder LA: More than just a barrier: urothelium as a drug target for urinary bladder pain. Am J Physiol Renal Physiol 2005, 289:F489-F495.PubMedCrossRefGoogle Scholar
  20. 20.
    Sun Y, Chai TC: Upregulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol 2004, 171:448–452.PubMedCrossRefGoogle Scholar
  21. 21.
    Tempest HV, Dixon AK, Turner WH, et al.: P2X and P2X receptor expression in human bladder urothelium and changes in interstitial cystitis. BJU Int 2004, 93:1344–1348.PubMedCrossRefGoogle Scholar
  22. 22.
    Beckel JM, Kanai A, Lee SJ, et al.: Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells. Am J Physiol Renal Physiol 2006, 290:F103-F110.PubMedCrossRefGoogle Scholar
  23. 23.
    Birder LA, Kanai AJ, de Groat WC, et al.: Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001, 98:13396–13401.PubMedCrossRefGoogle Scholar
  24. 24.
    Chess-Williams R: Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 2002, 22:133–145.PubMedCrossRefGoogle Scholar
  25. 25.
    Sun Y, Keay S, Dedeyne P, et al.: Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J Urol 2001, 166:1951–1956.PubMedCrossRefGoogle Scholar
  26. 26.
    Sun Y, Chai TC: Augmented Extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis. Am J Physiol Cell Physiol 2006, 290:C27-C34. Building on the work from Sun et al. [25], IC BUCs also responded to increased extracellular ATP with even more ATP release. A “vicious cycle” between stretch and autocrine action of ATP is proposed to underlie bladder hypersensation in IC.PubMedCrossRefGoogle Scholar
  27. 27.
    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 Physiol 1998, 275:F226-F229.PubMedGoogle Scholar
  28. 28.
    Hegde SS: Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 2006, 147:S80-S87.PubMedCrossRefGoogle Scholar
  29. 29.
    Vlaskovska M, Kasakov L, Rong W, et al.: P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 2001, 21:5670–5677.PubMedGoogle Scholar
  30. 30.
    Cockayne DA, Hamilton SG, Zhu QM, et al.: Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 2000, 407:1011–1015.PubMedCrossRefGoogle Scholar
  31. 31.
    Cockayne DA, Dunn PM, Zhong Y, et al.: P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol 2005, 567:621–639.PubMedCrossRefGoogle Scholar
  32. 32.
    Wang EC, Lee JM, Ruiz WG, et al.: ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J Clin Invest 2005, 115:2412–2422.PubMedCrossRefGoogle Scholar
  33. 33.
    Sun Y, Chen M, Lowentritt BH, et al.: EGF and HB-EGF modulate inward potassium current in human bladder urothelial cells from normal and interstitial cystitis patients. Am J Physiol Cell Physiol 2006, July 12; [Epub ahead of print].Google Scholar
  34. 34.
    Busse R, Edwards G, Feletou M, et al.: EDHF: bringing the concepts together. Trends Pharmacol Sci 2002, 23:374–380.PubMedCrossRefGoogle Scholar
  35. 35.
    Meredith AL, Thorneloe KS, Werner ME, et al.: Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 2004, 279:36746–36752.PubMedCrossRefGoogle Scholar
  36. 36.
    Slobodov G, Feloney M, Gran C, et al.: Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis. J Urol 2004, 171:1554–1558. These authors found decreased expression of proteins that provide impermeability in IC BU.PubMedCrossRefGoogle Scholar
  37. 37.
    Erickson DR, Herb N, Ordille S, et al.: A new direct test of bladder permeability. J Urol 2000: 164:419–422.PubMedCrossRefGoogle Scholar
  38. 38.
    Buffington CA, Woodworth BE: Excretion of fluorescein in the urine of women with interstitial cystitis. J Urol 1997, 158:786–789.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang C, Wang J, Koch K, Keay S: Regulation of tight junction proteins and bladder epithelial paracellular permeability by an antiproliferative factor from patients with interstitial cystitis. J Urol 2005, 174:2382–2387. These investigators determined that APF decreased the expression of tight junction proteins in cultured BUCs. The results confirm the immunohistochemical experiments done in the study by Slobodov et al. [36].PubMedCrossRefGoogle Scholar
  40. 40.
    Keay S, Szekely Z, Conrads TP, et al.: An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc Natl Acad Sci U S A 2004, 101:11803–11808. This is the definitive work that revealed the peptide and glycosylation sequence of APF.PubMedCrossRefGoogle Scholar
  41. 41.
    Keay S, Zhang CO, Hise MK, et al.: A diagnostic in vitro urine assay for interstitial cystitis. Urology 1998, 52:974–978.PubMedCrossRefGoogle Scholar
  42. 42.
    Keay S, Zhang CO, Shoenfelt J, et al.: Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology 2001, 57:9–14.PubMedCrossRefGoogle Scholar
  43. 43.
    Keay S, Zhang CO, Shoenfelt JL, Chai TC: Decreased in vitro proliferation of bladder epithelial cells from patients with interstitial cystitis. Urology 2003, 61:1278–1284.PubMedCrossRefGoogle Scholar
  44. 44.
    Keay S, Zhang CO, Kagen DI, et al.: Concentrations of specific epithelial growth factors in the urine of interstitial cystitis patients and controls. J Urol 1997, 158:1983–1988.PubMedCrossRefGoogle Scholar
  45. 45.
    Keay S, Kleinberg M, Zhang CO, et al.: Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production. J Urol 2000, 164:2112–2118.PubMedCrossRefGoogle Scholar
  46. 46.
    Erickson DR, Xie SX, Bhavanandan VP, et al.: A comparison of multiple urine markers for interstitial cystitis. J Urol 2002, 167:2461–2469.PubMedCrossRefGoogle Scholar
  47. 47.
    Lehrfeld TJ, Sun Y, Chai TC: Link between cytokine expression and augmented purinergic signaling in interstitial cystitis (IC) bladder urothelial cells (BUC) [Abstract 286]. J Urol 2006, 175:95.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  • Emmanuel Graham
  • Toby C. Chai
    • 1
  1. 1.Division of UrologyUniversity of Maryland Medical CenterBaltimoreUSA

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