Skip to main content
SpringerLink
Log in
Book cover

Urinary Tract pp 233–254Cite as

Interstitial Cells of Cajal in the Urinary Tract

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 2011))

Abstract

The study of novel interstitial cells in the tissues of the urinary tract has defined advances in the field in the last decade. These intriguing cells belong to the same family as the better known interstitial cells of Cajal (ICC) of the gastrointestinal tract, and their discovery has been interpreted to suggest that pacemaker cells may be present in the urinary tract, driving the spontaneous or myogenic activity of the neighboring smooth muscle. This scenario may be true for the urethra where ICC have been described as “loose pacemakers” providing multiple, random inputs to modulate urethral smooth muscle activity. However, there is a paucity of direct evidence available to support this hypothesis in the bladder (where the smooth muscle cells are spontaneously active) or the renal pelvis (where atypical smooth muscle cells are the pacemakers), and it now seems more likely that urinary tract ICC act as modulators of smooth muscle activity.

Interestingly, the literature suggests that the role of urinary tract ICC may be more apparent in pathophysiological conditions such as the overactive bladder. Several reports have indicated that the numbers of ICC present in overactive bladder tissues are greater than those from normal tissues; moreover, the contractility of tissues from overactive bladders in vitro appears to be more sensitive to the Kit antagonist, glivec, than those from normal bladder. Future research on urinary tract ICC in the short to medium term is likely to be dynamic and exciting and will lead to increasing our understanding of the roles of these cells in both normal and dysfunctional bladder.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Anderson UA, Carson C, McCloskey KD (2009) KCNQ currents and their contribution to resting membrane potential and the excitability of interstitial cells of Cajal from the guinea pig bladder. J Urol 182:330–336

    Article  CAS  PubMed  Google Scholar 

  • Azadzoi KM, Tarcan T, Kozlowski R, Krane RJ, Siroky MB (1999) Overactivity and structural changes in the chronically ischemic bladder. J Urol 162:1768–1778

    Article  CAS  PubMed  Google Scholar 

  • Biers SM, Reynard JM, Doore T, Brading AF (2006) The functional effects of a c-kit tyrosine inhibitor on guinea-pig and human detrusor. BJU Int 97(3):612–616

    Article  CAS  PubMed  Google Scholar 

  • Brading AF (1999) The physiology of the mammalian urinary outflow tract. Exp Physiol 84(1):215–221

    CAS  PubMed  Google Scholar 

  • Brading AF, 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  PubMed  Google Scholar 

  • Bradley E, Hollywood MA, Johnston L, Large RJ, Matsuda T, Baba A, McHale NG, Thornbury KD, Sergeant GP (2006) Contribution of reverse Na+-Ca2+ exchange to spontaneous activity in interstitial cells of Cajal in the rabbit urethra. J Physiol 574:651–661

    Article  CAS  PubMed  Google Scholar 

  • Cajal SR (1911) Histologie du système nerveux de l'homme et des vertébrés, vol 2. Maloine, Paris, pp 891–942

    Google Scholar 

  • Callahan SM, Creed KE (1981) Electrical and mechanical activity of the isolated lower urinary tract of the guinea-pig. Br J Pharmacol 74:353–358

    CAS  PubMed  Google Scholar 

  • Constantinou CE, Silvert MA, Gosling J (1977) Pacemaker system in the control of ureteral peristaltic rate in the multicalyceal kidney of the pig. Invest Urol 14:440–441

    CAS  PubMed  Google Scholar 

  • Constantinou CE, Neubarth JL, Mensah-Dwumah M (1978) Frequency gradient in the autorhythmicity of the pyeloureteral pacemaker system. Experientia 34:614–615

    Article  CAS  PubMed  Google Scholar 

  • Cotton KD, Hollywood MA, McHale NG, Thornbury KD (1997) Ca2+ current and Ca2+-activated chloride current in isolated smooth muscle cells of the sheep urethra. J Physiol 505:121–131

    Article  CAS  PubMed  Google Scholar 

  • Cunningham RMJ, Larkin P, McCloskey KD (2011) Ultrastructural Properties of Interstitial Cells of Cajal in the Guinea Pig Bladder. J Urol (in press)

    Google Scholar 

  • David SG, Cebrian C, Vaughan ED Jr, Herzlinger D (2005) c-kit and ureteral peristalsis. J Urol 173:292–295

    Google Scholar 

  • Davidson RA, McCloskey KD (2005) Morphology and localization of interstitial cells in the guinea-pig bladder: structural relationships with smooth muscle and neurons. J Urol 173:1385–1390

    Article  PubMed  Google Scholar 

  • Everaerts W, Sepúlveda MR, Gevaert T, Roskams T, Nilius B, De Ridder D (2009) Where is TRPV1 expressed in the bladder, do we see the real channel? Naunyn Schmiedebergs Arch Pharmacol 379:421–425

    Article  CAS  PubMed  Google Scholar 

  • García-Pascual A, Sancho M, Costa G, Triguero D (2008) Interstitial cells of Cajal in the urethra are cGMP-mediated targets of nitrergic neurotransmission. Am J Physiol Renal Physiol 295:F971–F983

    Article  PubMed  Google Scholar 

  • Gillespie JI, Markerink-van Ittersum M, de Vente J (2004) cGMP-generating cells in the bladder wall: identification of distinct networks of interstitial cells. BJU Int 94(7):1114–1124

    Article  PubMed  Google Scholar 

  • Gosling JA, Dixon JS (1971) Morphologic evidence that rhe renal calyx and pelvis control ureteric activity in the rabbit. Am J Anat 130:393–408

    Article  CAS  PubMed  Google Scholar 

  • Gosling JA, Dixon JS (1974) Species variation in the location of upper urinary tract pacemaker cells. Invest Urol 11:418–423

    CAS  PubMed  Google Scholar 

  • Grol S, Essers PB, van Koeveringe GA, Martinez-Martinez P, de Vente J, Gillespie JI (2009) M(3) muscarinic receptor expression on suburothelial interstitial cells. BJU Int 104:398–405

    Article  CAS  PubMed  Google Scholar 

  • Hashitani H, Suzuki H (2007) Properties of spontaneous Ca2+ transients recorded from interstitial cells of Cajal-like cells of the rabbit urethra in situ. J Physiol 583:505–519

    Article  CAS  PubMed  Google Scholar 

  • Hashitani H, Van Helden DF, Suzuki H (1996) Properties of spontaneous depolarizations in circular smooth muscle cells of rabbit urethra. Br J Pharmacol 118:1627–1632

    CAS  PubMed  Google Scholar 

  • Hashitani H, Yanai Y, Suzuki H (2004) Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the guinea-pig urinary bladder. J Physiol 559:567–581

    Article  CAS  PubMed  Google Scholar 

  • Horowitz B, Ward SM, Sanders KM (1999) Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu Rev Physiol 61:19–43

    Article  CAS  PubMed  Google Scholar 

  • Ikeda Y, Fry C, Hayashi F, Stolz D, Griffiths D, Kanai A (2007) Role of gap junctions in spontaneous activity of the rat bladder. Am J Physiol Renal Physiol 293:F1018–F1025

    Article  CAS  PubMed  Google Scholar 

  • Johnston L, Sergeant GP, Hollywood MA, Thornbury KD, McHale NG (2005) Calcium oscillations in interstitial cells of the rabbit urethra. J Physiol 565:449–461

    Article  CAS  PubMed  Google Scholar 

  • Johnston L, Carson C, Lyons AD, Davidson RA, McCloskey KD (2008) Cholinergic-induced Ca2+ signaling in interstitial cells of Cajal from the guinea pig bladder. Am J Physiol Renal Physiol 294:F645–F655

    Article  CAS  PubMed  Google Scholar 

  • Johnston L, Woolsey S, O’Kane H, Duggan B, Keane P, McCloskey KD (2010) Expression of kit-positive interstitial cells of cajal in human bladder. J Urol 184:370–377

    Article  PubMed  Google Scholar 

  • de Jongh R, van Koeveringe GA, van Kerrebroeck PE, Markerink-van Ittersum M, de Vente J, Gillespie JI (2007) The effects of exogenous prostaglandins and the identification of constitutive cyclooxygenase I and II immunoreactivity in the normal guinea pig bladder. BJU Int 100:419–429

    Article  PubMed  Google Scholar 

  • de Jongh R, Grol S, van Koeveringe G, van Kerrebroeck P, de Vente J, Gillespie J (2009) The localisation of cyclo-oxygenase immuno-reactivity (COX I-IR) to the urothelium and to interstitial cells in the bladder wall. J Cell Mol Med 13:3069–3081

    Article  PubMed  Google Scholar 

  • Klemm MF, Exintaris B, Lang RJ (1999) Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. J Physiol 519:867–884

    Article  CAS  PubMed  Google Scholar 

  • Komuro T (1999) Comparative morphology of interstitial cells of Cajal: ultrastructural characterization. Microsc Res Tech 47(4):267–285

    Article  CAS  PubMed  Google Scholar 

  • Komuro T, Seki K, Horiguchi K (1999) Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol 62:295–316

    Article  CAS  PubMed  Google Scholar 

  • Kubota Y, Kajioka S, Biers SM, Yokota E, Kohri K, Brading AF (2004) Investigation of the effect of the c-kit inhibitor Glivec on isolated guinea-pig detrusor preparations. Auton Neurosci 30(115):64–73

    Article  Google Scholar 

  • Kubota Y, Biers SM, Kohri K, Brading AF (2006) Effects of imatinib mesylate (Glivec) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder. Neurourol Urodyn 25:205–210

    Article  CAS  PubMed  Google Scholar 

  • Kubota Y, Hashitani H, Shirasawa N, Kojima Y, Sasaki S, Mabuchi Y, Soji T, Suzuki H, Kohri K (2008) Altered distribution of interstitial cells in the guinea pig bladder following bladder outlet obstruction. Neurourol Urodyn 27:330–340

    Article  PubMed  Google Scholar 

  • Lang RJ, Exintaris B, Teele ME, Harvey J, Klemm MF (1998) Electrical basis of peristalsis in the mammalian upper urinary tract. Clin Exp Pharmacol Physiol 25(5):310–321

    Article  CAS  PubMed  Google Scholar 

  • Lang RJ, Klemm MF (2005) Interstitial cell of Cajal-like cells in the upper urinary tract. J Cell Mol Med 9:543–556

    Article  CAS  PubMed  Google Scholar 

  • Lang RJ, Hashitani H, Tonta MA, Parkington HC, Suzuki H (2007a) Spontaneous electrical and Ca2+ signals in typical and atypical smooth muscle cells and interstitial cell of Cajal-like cells of mouse renal pelvis. J Physiol 583:1049–1068

    Article  CAS  PubMed  Google Scholar 

  • Lang RJ, Zoltkowski BZ, Hammer JM, Meeker WF, Wendt I (2007b) Electrical characterization of interstitial cells of Cajal-like cells and smooth muscle cells isolated from the mouse ureteropelvic junction. J Urol 177:1573–1580

    Article  CAS  PubMed  Google Scholar 

  • Lang RJ, Hashitani H, Tonta MA, Bourke JL, Parkington HC, Suzuki H (2010) Spontaneous electrical and Ca2+ signals in the mouse renal pelvis that drive pyeloureteric peristalsis. Clin Exp Pharmacol Physiol 37:509–515

    Article  CAS  PubMed  Google Scholar 

  • Lavoie B, Balemba OB, Nelson MT, Ward SM, Mawe GM (2007) Morphological and physiological evidence for interstitial cell of Cajal-like cells in the guinea pig gallbladder. J Physiol 579:487–501

    Article  CAS  PubMed  Google Scholar 

  • Lyons AD, Gardiner TA, McCloskey KD (2007) Kit-positive interstitial cells in the rabbit urethra: structural relationships with nerves and smooth muscle. BJU Int 99:687–694

    Article  PubMed  Google Scholar 

  • Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, Nishikawa S (1992) Requirement of c-kit for development of intestinal pacemaker system. Development 116:369–375

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • McCloskey KD (2006) Calcium currents in interstitial cells from the guinea-pig bladder. BJU Int 97:1338–1343

    Article  CAS  PubMed  Google Scholar 

  • McCloskey KD, Gurney AM (2002) Kit-positive cells in the guinea pig bladder. J Urol 168:832–836

    Article  PubMed  Google Scholar 

  • McCloskey KD, Anderson UA, Davidson RA, Bayguinov YR, Sanders KM, Ward SM (2009) Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice. Br J Pharmacol 156(2):273–283

    Article  CAS  PubMed  Google Scholar 

  • Metzger R, Schuster T, Till H, Stehr M, Franke FE, Dietz HG (2004) Cajal-like cells in the human upper urinary tract. J Urol 172:769–772

    Article  PubMed  Google Scholar 

  • Metzger R, Schuster T, Till H, Franke FE, Dietz HG (2005) Cajal-like cells in the upper urinary tract: comparative study in various species. Pediatr Surg Int 21:169–174

    Article  PubMed  Google Scholar 

  • Metzger R, Neugebauer A, Rolle U, Böhlig L, Till H (2008) c-Kit receptor (CD117) in the porcine urinary tract. Pediatr Surg Int 24:67–76

    Article  PubMed  Google Scholar 

  • Mukerji G, Yiangou Y, Grogono J, Underwood J, Agarwal SK, Khullar V, Anand P (2006) Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol 176:367–373

    Article  CAS  PubMed  Google Scholar 

  • Ost D, Roskams T, Van Der Aa F, De Ridder D (2002) Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers. J Urol 168:293–297

    Article  PubMed  Google Scholar 

  • Pezzone MA, Watkins SC, Alber SM, King WE, de Groat WC, Chancellor MB, Fraser MO (2003) Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract. Am J Physiol Renal Physiol 284(5):F925–F929

    Google Scholar 

  • Piaseczna Piotrowska A, Rolle U, Solari V, Puri P (2004) Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis-microcolon intestinal hypoperistalsis syndrome. BJU Int 94:143–146

    Article  PubMed  Google Scholar 

  • Rasmussen H, Rumessen JJ, Hansen A, Smedts F, Horn T (2009) Ultrastructure of Cajal-like interstitial cells in the human detrusor. Cell Tissue Res 335:517–527

    Article  PubMed  Google Scholar 

  • Roosen A, Datta SN, Chowdhury RA, Patel PM, Kalsi V, Elneil S, Dasgupta P, Kessler TM, Khan S, Panicker J, Fry CH, Brandner S, Fowler CJ, Apostolidis A (2009) Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin Type A treatment. Eur Urol 55:1440–1448

    Article  CAS  PubMed  Google Scholar 

  • Sanders KM (1996) A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111:492–515

    Article  CAS  PubMed  Google Scholar 

  • Sanders KM, Koh SD, Ward SM (2006) Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol 68:307–343

    Article  CAS  PubMed  Google Scholar 

  • Sanders KM, Ordög T, Ward SM (2002) Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 282(5):G747–G756

    CAS  PubMed  Google Scholar 

  • Sanders KM, Ordög T, Koh SD, Torihashi S, Ward SM (1999) Development and plasticity of interstitial cells of Cajal. Neurogastroenterol Motil 5:311–338

    Article  Google Scholar 

  • Sanders KM, Ward SM (2007) Kit mutants and gastrointestinal physiology. J Physiol 578:33–42

    Article  CAS  PubMed  Google Scholar 

  • Sergeant GP, Hollywood MA, McCloskey KD, Thornbury KD, McHale NG (2000) Specialized pacemaking cells in the rabbit urethra. J Physiol 526:359–366

    Article  CAS  PubMed  Google Scholar 

  • Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD (2001) Role of IP(3) in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Physiol Cell Physiol 280:C1349–C1356

    CAS  PubMed  Google Scholar 

  • Sergeant GP, Thornbury KD, McHale NG, Hollywood MA (2002) Characterization of norepinephrine-evoked inward currents in interstitial cells isolated from the rabbit urethra. Am J Physiol Cell Physiol 283:C885–C894

    CAS  PubMed  Google Scholar 

  • Sergeant GP, Bradley E, Thornbury KD, McHale NG, Hollywood MA (2008) Role of mitochondria in modulation of spontaneous Ca2+ waves in freshly dispersed interstitial cells of Cajal from the rabbit urethra. J Physiol 586:4631–4642

    Article  CAS  PubMed  Google Scholar 

  • Sergeant GP, Bradley E, Drumm B, Hollywood MA, McHale NG, Thornbury KD (2009) Regulation of spontaneous activity in interstitial cells of Cajal of the rabbit urethra by ATP. Proc Physiol Soc 15:C139

    Google Scholar 

  • Shafik A, El-Sibai O, Shafik AA, Shafik I (2004) Identification of interstitial cells of Cajal in human urinary bladder: concept of vesical pacemaker. Urology 64:809–813

    Article  PubMed  Google Scholar 

  • Smet PJ, Jonavicius J, Marshall VR, de Vente J (1996) 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 71:337–348

    Article  CAS  PubMed  Google Scholar 

  • Solari V, Piotrowska AP, Puri P (2003) Altered expression of interstitial cells of Cajal in congenital ureteropelvic junction obstruction. J Urol 170:2420–2422

    Article  PubMed  Google Scholar 

  • Sui GP, Rothery S, Dupont E, Fry CH, Severs NJ (2002) Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 90:118–129

    Article  CAS  PubMed  Google Scholar 

  • Sui GP, Wu C, Fry CH (2004) Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol 171:938–943

    Article  CAS  PubMed  Google Scholar 

  • Sui GP, Wu C, Fry CH (2006) Characterization of the purinergic receptor subtype on guinea-pig suburothelial myofibroblasts. BJU Int 97:1327–1331

    Article  CAS  PubMed  Google Scholar 

  • Sui GP, Wu C, Roosen A, Ikeda Y, Kanai AJ, Fry CH (2008) Modulation of bladder myofibroblast activity: implications for bladder function. Am J Physiol Renal Physiol 295:F688–F697

    Article  CAS  PubMed  Google Scholar 

  • Turner WH, Brading AF (1997) Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol Ther 75:77–110

    Article  CAS  PubMed  Google Scholar 

  • Wu C, Sui GP, Fry CH (2004) Purinergic regulation of guinea pig suburothelial myofibroblasts. J Physiol 559:231–243

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK

    Karen D. McCloskey

Authors
  1. Karen D. McCloskey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen D. McCloskey .

Editor information

Editors and Affiliations

  1. Wake Forest University, Medical Center Blvd., Winston-Salem, 27157-1088, North Carolina, USA

    Karl-Erik Andersson

  2. Academic Medical Center, Dept. Pharmacology & Pharmacotherapy, University of Amsterdam, Meibergdreef 15, Amsterdam, 1105 AZ, Netherlands

    Martin C. Michel

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

McCloskey, K.D. (2011). Interstitial Cells of Cajal in the Urinary Tract. In: Andersson, KE., Michel, M. (eds) Urinary Tract. Handbook of Experimental Pharmacology, vol 2011. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16499-6_11

Download citation

Publish with us

Policies and ethics

Search

Navigation