Immunohistochemistry as a paramount tool in research of normal urothelium, bladder cancer and bladder pain syndrome

Abstract

The urothelium, an epithelium of the urinary bladder, primarily functions as blood-urine permeability barrier. The urothelium has a very slow turn-over under normal conditions but is capable of extremely fast response to injury. During regeneration urothelium either restores normal function or undergoes altered differentiation pathways, the latter being the cause of several bladder diseases. In this review, we describe the structure of the apical plasma membrane that enables barrier function, the role of urothelium specific proteins uroplakins and the machinery for polarized membrane transports in terminally differentiated superficial umbrella cells. We address key markers, such as keratins, cancer stem cell markers, retinoic acid signalling pathway proteins and transient receptor potential channels and purinergic receptors that drive normal and altered differentiation in bladder cancer and bladder pain syndrome. Finally, we discuss uncertainties regarding research, diagnosis and treatment of bladder pain syndrome. Throughout the review, we emphasise the contribution of immunohistochemistry in advancing our understanding of processes in normal and diseased bladder as well as the most promising possibilities for improved bladder cancer and bladder pain syndrome management.

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References

Romih R, Korosec P, de Mello W, Jr., Jezernik K. Differentiation of epithelial cells in the urinary tract. Cell Tissue Res 2005;320:259-68. DOI: https://doi.org/10.1007/s00441-004-1005-4

Hicks RM. The mammalian urinary bladder: an accommodating organ. Biol Rev Camb Philos Soc 1975;50:215-46. DOI: https://doi.org/10.1111/j.1469-185X.1975.tb01057.x

Koss LG. The asymmetric unit membranes of the epithelium of the urinary bladder of the rat. An electron microscopic study of a mechanism of epithelial maturation and function. Lab Invest 1969;21:154-68.

Lewis SA, Diamond JM. Na+ transport by rabbit urinary bladder, a tight epithelium. J Membr Biol 1976;28:1-40. DOI: https://doi.org/10.1007/BF01869689

Denny-Brown D, Robertson EG. On the physiology of micturition. Brain 1933;56:149-90. DOI: https://doi.org/10.1093/brain/56.2.149

Apodaca G. The uroepithelium: not just a passive barrier. Traffic 2004;5:117-28. DOI: https://doi.org/10.1046/j.1600-0854.2003.00156.x

Birder LA. More than just a barrier: urothelium as a drug target for urinary bladder pain. Am J Physiol Renal Physio. 2005;289:F489-95. DOI: https://doi.org/10.1152/ajprenal.00467.2004

Burnstock G, Cocks T, Crowe R, Kasakov L. Purinergic innervation of the guinea-pig urinary bladder. Br J Pharmacol 1978;63:125-38. DOI: https://doi.org/10.1111/j.1476-5381.1978.tb07782.x

Winder M, Tobin G, Zupancic D, Romih R. Signalling molecules in the urothelium. Biomed Res Int 2014;2014:297295. DOI: https://doi.org/10.1155/2014/297295

Apodaca G, Balestreire E, Birder LA. The uroepithelial-associated sensory web. Kidney Int 2007;72:1057-64. DOI: https://doi.org/10.1038/sj.ki.5002439

Hicks RM. The fine structure of the transitional epithelium of rat ureter. J Cell Biol 1965;26:25-48. DOI: https://doi.org/10.1083/jcb.26.1.25

Porter KR, Kenyon K, Badenhausen S. Specializations of the unit membrane. Protoplasma 1967;63:262-74. DOI: https://doi.org/10.1007/BF01248042

Caruthers JS, Bonneville MA. Isolation and characterization of the urothelial lumenal plasma membrane. J Cell Biol 1977;73:382-99. DOI: https://doi.org/10.1083/jcb.73.2.382

Hicks RM, Ketterer B. Hexagonal lattice of subunits in the thick luminal membrane of the rat urinary bladder. Nature 1969;224:1304-5. DOI: https://doi.org/10.1038/2241304a0

Zupancic D, Romih R, Robenek H, Zuzek Rozman K, Samardzija Z, Kostanjsek R, et al. Molecular ultrastructure of the urothelial surface: insights from a combination of various microscopic techniques. Microsc Res Tech 2014;77:896-901. DOI: https://doi.org/10.1002/jemt.22412

Walz T, Häner M, Wu XR, Henn C, Engel A, Sun TT, et al. Towards the molecular architecture of the asymmetric unit membrane of the mammalian urinary bladder epithelium: a closed "twisted ribbon" structure. J Mol Biol 1995;248:887-900. DOI: https://doi.org/10.1006/jmbi.1995.0269

Veranic P, Romih R, Jezernik K. What determines differentiation of urothelial umbrella cells? Eur J Cell Biol 2004;83:27-34. DOI: https://doi.org/10.1078/0171-9335-00351

Romih R, Veranic P, Jezernik K. Appraisal of differentiation markers in urothelial cells. Appl Immunohistochem Mol Morphol 2002;10:339-43. DOI: https://doi.org/10.1097/00129039-200212000-00009

Kachar B, Liang F, Lins U, Ding M, Wu XR, Stoffler D, 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. DOI: https://doi.org/10.1006/jmbi.1998.2304

Wu XR, Manabe M, Yu J, Sun TT. Large scale purification and immunolocalization of bovine uroplakins I, II, and III. Molecular markers of urothelial differentiation. J Biol Chem 1990;265:19170-9.

Wu XR, Lin JH, Walz T, Haner M, Yu J, Aebi U, et al. Mammalian uroplakins. A group of highly conserved urothelial differentiation-related membrane proteins. J Biol Chem 1994;269:13716-24.

Min G, Zhou G, Schapira M, Sun TT, Kong XP. Structural basis of urothelial permeability barrier function as revealed by Cryo-EM studies of the 16 nm uroplakin particle. J Cell Sci 2003;116:4087-94. DOI: https://doi.org/10.1242/jcs.00811

Yu J, Manabe M, Wu XR, Xu C, Surya B, Sun TT. Uroplakin I: a 27-kD protein associated with the asymmetric unit membrane of mammalian urothelium. J Cell Biol 1990;111:1207-16. DOI: https://doi.org/10.1083/jcb.111.3.1207

Wu XR, Lin JH, Walz T, Häner M, Yu J, Aebi U, et al. Mammalian uroplakins. A group of highly conserved urothelial differentiation-related membrane proteins. J Biol Chem 1994;269:13716-24. DOI: https://doi.org/10.1016/S0021-9258(17)36889-8

Yu J, Lin JH, Wu XR, Sun TT. Uroplakins Ia and Ib, two major differentiation products of bladder epithelium, belong to a family of four transmembrane domain (4TM) proteins. J Cell Biol 1994;125:171-82. DOI: https://doi.org/10.1083/jcb.125.1.171

Hu CC, Liang FX, Zhou G, Tu L, Tang CH, Zhou J, et al. Assembly of urothelial plaques: tetraspanin function in membrane protein trafficking. Mol Biol Cell 2005;16:3937-50. DOI: https://doi.org/10.1091/mbc.e05-02-0136

Deng FM, Liang FX, Tu L, Resing KA, Hu P, Supino M, et al. Uroplakin IIIb, a urothelial differentiation marker, dimerizes with uroplakin Ib as an early step of urothelial plaque assembly. J Cell Biol 2002;159:685-94. DOI: https://doi.org/10.1083/jcb.200204102

Liang FX, Riedel I, Deng FM, Zhou G, Xu C, Wu XR, et al. Organization of uroplakin subunits: transmembrane topology, pair formation and plaque composition. Biochem J 2001;355:13-8. DOI: https://doi.org/10.1042/bj3550013

Tu L, Sun TT, Kreibich G. Specific heterodimer formation is a prerequisite for uroplakins to exit from the endoplasmic reticulum. Mol Biol Cell 2002;13:4221-30. DOI: https://doi.org/10.1091/mbc.e02-04-0211

Tu L, Kong XP, Sun TT, Kreibich G. Integrity of all four transmembrane domains of the tetraspanin uroplakin Ib is required for its exit from the ER. J Cell Sci 2006;119:5077-86. DOI: https://doi.org/10.1242/jcs.03285

Lin JH, Wu XR, Kreibich G, Sun TT. Precursor sequence, processing, and urothelium-specific expression of a major 15-kDa protein subunit of asymmetric unit membrane. J Biol Chem 1994;269:1775-84. DOI: https://doi.org/10.1016/S0021-9258(17)42095-3

Hu CC, Bachmann T, Zhou G, Liang FX, Ghiso J, Kreibich G, et al. Assembly of a membrane receptor complex: roles of the uroplakin II prosequence in regulating uroplakin bacterial receptor oligomerization. Biochem J 2008;414:195-203. DOI: https://doi.org/10.1042/BJ20080550

Lewis SA. Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol Renal Physiol 2000;278:F867-74. DOI: https://doi.org/10.1152/ajprenal.2000.278.6.F867

Hudoklin S, Jezernik K, Neumüller J, Pavelka M, Romih R. Electron tomography of fusiform vesicles and their organization in urothelial cells. PLoS One 2012;7:e32935. DOI: https://doi.org/10.1371/journal.pone.0032935

Hudoklin S, Jezernik K, Neumuller J, Pavelka M, Romih R. Urothelial plaque formation in post-Golgi compartments. PLoS One 2011;6:e23636. DOI: https://doi.org/10.1371/journal.pone.0023636

Veranic P, Jezernik K. Trajectorial organisation of cytokeratins within the subapical region of umbrella cells. Cell Motil Cytoskeleton 2002;53:317-25. DOI: https://doi.org/10.1002/cm.10077

Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, et al. Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases. J Cell Biol 2004;167:1195-204. DOI: https://doi.org/10.1083/jcb.200406025

Zhou G, Liang FX, Romih R, Wang Z, Liao Y, Ghiso J, et al. MAL facilitates the incorporation of exocytic uroplakin-delivering vesicles into the apical membrane of urothelial umbrella cells. Mol Biol Cell 2012;23:1354-66. DOI: https://doi.org/10.1091/mbc.e11-09-0823

Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998;22:1435-48. DOI: https://doi.org/10.1097/00000478-199812000-00001

Wang C, Ross WT, Mysorekar IU. Urothelial generation and regeneration in development, injury, and cancer. Dev Dyn 2017;246:336-43. DOI: https://doi.org/10.1002/dvdy.24487

Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol 2017;71:96-108. DOI: https://doi.org/10.1016/j.eururo.2016.06.010

Huang HY, Shariat SF, Sun TT, Lepor H, Shapiro E, Hsieh JT, et al. Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome. Hum Pathol 2007;38:1703-13. DOI: https://doi.org/10.1016/j.humpath.2007.04.003

Wu RL, Osman I, Wu XR, Lu ML, Zhang ZF, Liang FX, et al. Uroplakin II gene is expressed in transitional cell carcinoma but not in bilharzial bladder squamous cell carcinoma: alternative pathways of bladder epithelial differentiation and tumor formation. Cancer Res 1998;58:1291-7.

Zupancic D, Romih R. Heterogeneity of uroplakin localization in human normal urothelium, papilloma and papillary carcinoma. Radiol Oncol 2013;47:338-45. DOI: https://doi.org/10.2478/raon-2013-0052

Zupancic D, Zakrajsek M, Zhou G, Romih R. Expression and localization of four uroplakins in urothelial preneoplastic lesions. Histochem Cell Biol 2011;136:491-500. DOI: https://doi.org/10.1007/s00418-011-0857-4

Achtstätter T, Moll R, Moore B, Franke WW. Cytokeratin polypeptide patterns of different epithelia of the human male urogenital tract: immunofluorescence and gel electrophoretic studies. J Histochem Cytochem 1985;33:415-26. DOI: https://doi.org/10.1177/33.5.2580881

Schaafsma HE, Ramaekers FC, van Muijen GN, Ooms EC, Ruiter DJ. Distribution of cytokeratin polypeptides in epithelia of the adult human urinary tract. Histochemistry 1989;91:151-9. DOI: https://doi.org/10.1007/BF00492389

Moll R, Schiller DL, Franke WW. Identification of protein IT of the intestinal cytoskeleton as a novel type I cytokeratin with unusual properties and expression patterns. J Cell Biol 1990;111:567-80. DOI: https://doi.org/10.1083/jcb.111.2.567

Southgate J, Harnden P, Trejdosiewicz LK. Cytokeratin expression patterns in normal and malignant urothelium: a review of the biological and diagnostic implications. Histol Histopathol 1999;14:657-64.

McKenney JK, Desai S, Cohen C, Amin MB. Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens. Am J Surg Pathol 2001;25:1074-8. DOI: https://doi.org/10.1097/00000478-200108000-00013

Van Batavia J, Yamany T, Molotkov A, Dan H, Mansukhani M, Batourina E, et al. Bladder cancers arise from distinct urothelial sub-populations. Nat Cell Biol 2014;16:982-91. DOI: https://doi.org/10.1038/ncb3038

Lin C, Yin Y, Stemler K, Humphrey P, Kibel AS, Mysorekar IU, et al. Constitutive β-catenin activation induces male-specific tumorigenesis in the bladder urothelium. Cancer Res 2013;73:5914-25. DOI: https://doi.org/10.1158/0008-5472.CAN-12-4198

Shin K, Lim A, Zhao C, Sahoo D, Pan Y, Spiekerkoetter E, et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 2014;26:521-33. DOI: https://doi.org/10.1016/j.ccell.2014.09.001

Doldo E, Costanza G, Agostinelli S, Tarquini C, Ferlosio A, Arcuri G, et al. Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins. Biomed Res Int 2015;2015:624627. DOI: https://doi.org/10.1155/2015/624627

Mongan NP, Gudas LJ. Diverse actions of retinoid receptors in cancer prevention and treatment. Differentiation 2007;75:853-70. DOI: https://doi.org/10.1111/j.1432-0436.2007.00206.x

Liang FX, Bosland MC, Huang H, Romih R, Baptiste S, Deng FM, et al. Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement. J Cell Biol 2005;171:835-44. DOI: https://doi.org/10.1083/jcb.200505035

Tang JE, Wang RJ, Zhong H, Yu B, Chen Y. Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies. World J Surg Oncol 2014;12:130. DOI: https://doi.org/10.1186/1477-7819-12-130

Mahmoud LA, Robinson WA. Vitamin A levels in human bladder cancer. Int J Cancer 1982;30:143-5. DOI: https://doi.org/10.1002/ijc.2910300203

Wu S, Liu Y, Michalek JE, Mesa RA, Parma DL, Rodriguez R, et al. Carotenoid intake and circulating carotenoids are inversely associated with the risk of bladder cancer: A dose-response meta-analysis. Adv Nutr 2020;11:630-43. DOI: https://doi.org/10.1093/advances/nmz120

Zupancic D, Korac-Prlic J, Kreft ME, Frankovic L, Vilovic K, Jeruc J, et al. Vitamin A rich diet diminishes early urothelial carcinogenesis by altering retinoic acid signaling. Cancers (Basel) 2020;12:1712. DOI: https://doi.org/10.3390/cancers12071712

Simmons DP, Peach ML, Friedman JR, Green MM, Nicklaus MC, De Luca LM. Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action. Carcinogenesis 2006;27:693-707. DOI: https://doi.org/10.1093/carcin/bgi235

Boorjian S, Tickoo SK, Mongan NP, Yu H, Bok D, Rando RR, et al. Reduced lecithin: retinol acyltransferase expression correlates with increased pathologic tumor stage in bladder cancer. Clin Cancer Res 2004;10:3429-37. DOI: https://doi.org/10.1158/1078-0432.CCR-03-0756

van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008;53:60-7. DOI: https://doi.org/10.1016/j.eururo.2007.09.019

Homma Y. Interstitial cystitis, bladder pain syndrome, hypersensitive bladder, and interstitial cystitis/bladder pain syndrome - clarification of definitions and relationships. Int J Urol 2019;261:S20-4. DOI: https://doi.org/10.1111/iju.13970

Lee G, Romih R, Zupancic D. Cystitis: from urothelial cell biology to clinical applications. Biomed Res Int 2014;2014:473536. DOI: https://doi.org/10.1155/2014/473536

Zupancic D, Jezernik K, Vidmar G. Effect of melatonin on apoptosis, proliferation and differentiation of urothelial cells after cyclophosphamide treatment. J Pineal Res 2008;44:299-306. DOI: https://doi.org/10.1111/j.1600-079X.2007.00530.x

Kyung YS, Park HY, Lee G. Preservation of uroplakins by 2-mercaptoethanesulfonate in cyclophosphamide-induced rat cystitis. Arch Toxicol 2011;85:51-7. DOI: https://doi.org/10.1007/s00204-010-0523-y

Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013;93:653-80. DOI: https://doi.org/10.1152/physrev.00030.2012

Clapham DE, Julius D, Montell C, Schultz G. International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacol Rev 2005;57:427-50. DOI: https://doi.org/10.1124/pr.57.4.6

Merrill L, Gonzalez EJ, Girard BM, Vizzard MA. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol 2016;13:193-204. DOI: https://doi.org/10.1038/nrurol.2016.13

Charrua A, Cruz CD, Cruz F, Avelino A. Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis. J Urol 2007;177:1537-41. DOI: https://doi.org/10.1016/j.juro.2006.11.046

Lazzeri M, Vannucchi MG, Zardo C, Spinelli M, Beneforti P, Turini D, et al. Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder. Eur Urol 2004;46:792-8. DOI: https://doi.org/10.1016/j.eururo.2004.08.007

Yamada T, Ugawa S, Ueda T, Ishida Y, Kajita K, Shimada S. Differential localizations of the transient receptor potential channels TRPV4 and TRPV1 in the mouse urinary bladder. J Histochem Cytochem 2009;57:277-87. DOI: https://doi.org/10.1369/jhc.2008.951962

Dornelles FN, Andrade EL, Campos MM, Calixto JB. Role of CXCR2 and TRPV1 in functional, inflammatory and behavioural changes in the rat model of cyclophosphamide-induced haemorrhagic cystitis. Br J Pharmacol 2014;171:452-67. DOI: https://doi.org/10.1111/bph.12467

Park JS, Jung HD, Cho YS, Jin MH, Hong CH. Neonatal bladder irritation is associated with vanilloid receptor TRPV1 expression in adult rats. Int Neurourol J 2018;22:169-76. DOI: https://doi.org/10.5213/inj.1836020.101

Yu W, Hill WG, Apodaca G, Zeidel ML. Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium. Am J Physiol Renal Physiol 2011;300:F49-59. DOI: https://doi.org/10.1152/ajprenal.00349.2010

Everaerts W, Sepúlveda MR, Gevaert T, Roskams T, Nilius B, De Ridder D. Where is TRPV1 expressed in the bladder, do we see the real channel? Naunyn Schmiedebergs Arch Pharmacol 2009;379:421-5. DOI: https://doi.org/10.1007/s00210-008-0391-7

Ikeda Y, Birder L, Buffington C, Roppolo J, Kanai A. Mucosal muscarinic receptors enhance bladder activity in cats with feline interstitial cystitis. J Urol 2009;181:1415-22. DOI: https://doi.org/10.1016/j.juro.2008.10.138

Sánchez-Freire V, Blanchard MG, Burkhard FC, Kessler TM, Kellenberger S, Monastyrskaya K. Acid-sensing channels in human bladder: expression, function and alterations during bladder pain syndrome. J Urol 2011;186:1509-16. DOI: https://doi.org/10.1016/j.juro.2011.05.047

Janssen DA, Jansen CJ, Hafmans TG, Verhaegh GW, Hoenderop JG, Heesakkers JP, et al. TRPV4 channels in the human urogenital tract play a role in cell junction formation and epithelial barrier. Acta Physiol (Oxf) 2016;218:38-48. DOI: https://doi.org/10.1111/apha.12701

Sterle I, Zupancic D, Romih R. Correlation between Urothelial differentiation and sensory proteins P2X3, P2X5, TRPV1, and TRPV4 in normal urothelium and papillary carcinoma of human bladder. Biomed Res Int. 2014;2014:805236. DOI: https://doi.org/10.1155/2014/805236

Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci USA 2010;107:19084-9. DOI: https://doi.org/10.1073/pnas.1005333107

Charrua A, Cruz CD, Jansen D, Rozenberg B, Heesakkers J, Cruz F. Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis. BJU Int 2015;115:452-60. DOI: https://doi.org/10.1111/bju.12861

Janssen DA, Hoenderop JG, Jansen KC, Kemp AW, Heesakkers JP, Schalken JA. The mechanoreceptor TRPV4 is localized in adherence junctions of the human bladder urothelium: a morphological study. J Urol 2011;186:1121-7. DOI: https://doi.org/10.1016/j.juro.2011.04.107

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:F1084-91. DOI: https://doi.org/10.1152/ajprenal.00118.2004

Svennersten K, Hallen-Grufman K, de Verdier PJ, Wiklund NP, Poljakovic M. Localization of P2X receptor subtypes 2, 3 and 7 in human urinary bladder. BMC Urol 2015;15:81. DOI: https://doi.org/10.1186/s12894-015-0075-9

Vial C, Evans RJ. P2X receptor expression in mouse urinary bladder and the requirement of P2X(1) receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. Br J Pharmacol 2000;131:1489-95. DOI: https://doi.org/10.1038/sj.bjp.0703720

Dunton CL, Purves JT, Hughes FM, Jin H, Nagatomi J. Elevated hydrostatic pressure stimulates ATP release which mediates activation of the NLRP3 inflammasome via P2X. Int Urol Nephrol 2018;50:1607-17. DOI: https://doi.org/10.1007/s11255-018-1948-0

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. DOI: https://doi.org/10.1172/JCI24086

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. DOI: https://doi.org/10.1111/j.1464-410X.2007.07251.x

Ferguson AC, Sutton BW, Boone TB, Ford AP, Munoz A. Inhibition of urothelial P2X3 receptors prevents desensitization of purinergic detrusor contractions in the rat bladder. BJU Int 2015;116:293-301. DOI: https://doi.org/10.1111/bju.13003

Studeny S, Torabi A, Vizzard MA. P2X2 and P2X3 receptor expression in postnatal and adult rat urinary bladder and lumbosacral spinal cord. Am J Physiol Regul Integr Comp Physiol 2005;289:R1155-68. DOI: https://doi.org/10.1152/ajpregu.00234.2005

Liu M, Xu YF, Feng Y, Yang FQ, Luo J, Zhai W, et al. Epigallocatechin gallate attenuates interstitial cystitis in human bladder urothelium cells by modulating purinergic receptors. J Surg Res 2013;183:397-404. DOI: https://doi.org/10.1016/j.jss.2012.11.041

Tempest HV, Dixon AK, Turner WH, Elneil S, Sellers LA, Ferguson DR. P2X and P2X receptor expression in human bladder urothelium and changes in interstitial cystitis. BJU Int 2004;93:1344-8. DOI: https://doi.org/10.1111/j.1464-410X.2004.04858.x

Sun Y, Chai TC. Up-regulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol 2004;171:448-52. DOI: https://doi.org/10.1097/01.ju.0000099660.46774.3c

Sun Y, Keay S, Lehrfeld TJ, Chai TC. Changes in adenosine triphosphate-stimulated ATP release suggest association between cytokine and purinergic signaling in bladder urothelial cells. Urology 2009;74:1163-8. DOI: https://doi.org/10.1016/j.urology.2009.02.066

Yu W, Hill WG. Defining protein expression in the urothelium: a problem of more than transitional interest. Am J Physiol Renal Physiol 2011;301:F932-42. DOI: https://doi.org/10.1152/ajprenal.00334.2011

Kreft ME, Romih R, Kreft M, Jezernik K. Endocytotic activity of bladder superficial urothelial cells is inversely related to their differentiation stage. Differentiation 2009;77:48-59. DOI: https://doi.org/10.1016/j.diff.2008.09.011

Romih R, Jezernik K. Endocytosis during postnatal differentiation in superficial cells of the mouse urinary bladder epithelium. Cell Biol Int 1994;18:663-8. DOI: https://doi.org/10.1006/cbir.1994.1093

Liao Y, Tham DKL, Liang FX, Chang J, Wei Y, Sudhir PR, et al. Mitochondrial lipid droplet formation as a detoxification mechanism to sequester and degrade excessive urothelial membranes. Mol Biol Cell 2019;30:2969-84. DOI: https://doi.org/10.1091/mbc.E19-05-0284

Tratnjek L, Romih R, Kreft ME. Differentiation-dependent rearrangements of actin filaments and microtubules hinder apical endocytosis in urothelial cells. Histochem Cell Biol 2017;148:143-56. DOI: https://doi.org/10.1007/s00418-017-1566-4

Khandelwal P, Ruiz WG, Apodaca G. Compensatory endocytosis in bladder umbrella cells occurs through an integrin-regulated and RhoA- and dynamin-dependent pathway. EMBO J 2010;29:1961-75. DOI: https://doi.org/10.1038/emboj.2010.91

Winder M, Vesela R, Aronsson P, Patel B, Carlsson T. Autonomic receptor-mediated regulation of production and release of nitric oxide in normal and malignant human urothelial cells. Basic Clin Pharmacol Toxicol 2017;121:257-65. DOI: https://doi.org/10.1111/bcpt.12799

Hoffman DP, Shtengel G, Xu CS, Campbell KR, Freeman M, Wang L, et al. Correlative three-dimensional super-resolution and block-face electron microscopy of whole vitreously frozen cells. Science 2020;367:eaaz5357. DOI: https://doi.org/10.1126/science.aaz5357

Möbius W, Posthuma G. Sugar and ice: Immunoelectron microscopy using cryosections according to the Tokuyasu method. Tissue Cell 2019;57:90-102. DOI: https://doi.org/10.1016/j.tice.2018.08.010

Kreft ME, Di Giandomenico D, Beznoussenko GV, Resnik N, Mironov AA, Jezernik K. Golgi apparatus fragmentation as a mechanism responsible for uniform delivery of uroplakins to the apical plasma membrane of uroepithelial cells. Biol Cell 2010;102:593-607. DOI: https://doi.org/10.1042/BC20100024

Kreft ME, Robenek H. Freeze-fracture replica immunolabelling reveals urothelial plaques in cultured urothelial cells. PLoS One 2012;7:e38509. DOI: https://doi.org/10.1371/journal.pone.0038509

Zupancic D, Kreft ME, Sterle I, Romih R. Combined lectin- and immuno-histochemistry (CLIH) for applications in cell biology and cancer diagnosis: Analysis of human urothelial carcinomas. Eur J Histochem 2020;64:3141. DOI: https://doi.org/10.4081/ejh.2020.3141

Published
2021-03-24
Info
Issue
Section
Reviews
Supporting Agencies
Slovenian Research Agency ARRS
Keywords:
Urothelium, bladder cancer, bladder pain syndrome, uroplakins, keratins, retinoic acid, transient receptor potential channels, purinergic receptors
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How to Cite
Zupančič, D., & Romih, R. (2021). Immunohistochemistry as a paramount tool in research of normal urothelium, bladder cancer and bladder pain syndrome. European Journal of Histochemistry, 65(2). https://doi.org/10.4081/ejh.2021.3242