Elsevier

Autonomic Neuroscience

Volume 153, Issues 1–2, 16 February 2010, Pages 33-40
Autonomic Neuroscience

Urothelial signaling

https://doi.org/10.1016/j.autneu.2009.07.005Get rights and content

Abstract

Beyond serving as a simple barrier, there is growing evidence that the urinary bladder urothelium exhibits specialized sensory properties and play a key role in the detection and transmission of both physiological and nociceptive stimuli. These urothelial cells exhibit the ability to sense changes in their extracellular environment including the ability to respond to chemical, mechanical and thermal stimuli that may communicate the state of the urothelial environment to the underlying nervous and muscular systems. Here, we review the specialized anatomy of the urothelium and speculate on possible communication mechanisms from urothelial cells to various cell types within the bladder wall.

Section snippets

Anatomy and barrier function of the urothelium

The uroepithelium forms the interface between the urinary space and the underlying vasculature, connective, nervous, and muscular tissues. Urothelium is composed of at least three layers: a basal cell layer attached to a basement membrane, an intermediate layer, and a superficial or apical layer composed of large hexagonal cells (diameters of 25–250 μm) known as ‘umbrella cells’(Apodaca, 2004, Lewis, 2000). The umbrella cells are interconnected by tight junctions (which are composed of multiple

Urothelial heterogeneity

Studies of different species have shown that the major part of the urinary tract is lined with a fully differentiated urothelium (Sun, 2006). Findings in cultured cells reveal a distinct difference in morphology of ureteral and bladder urothelial cells, supporting a difference in cell lineage. There seems to be no apparent difference between the urothelium of the trigone compared to the detrusor. This is in contrast to the proximal urethra, a region in which a complete ‘barrier’ is unnecessary,

Evidence suggesting a role for urothelial cells in visceral sensation

While urothelial cells are often viewed as bystanders in the process of visceral sensation, recent evidence has supported the view that these cells function as primary transducers of some physical and chemical stimuli and are able to communicate with underlying cells including bladder nerves, smooth muscle and even inflammatory cells. (Fig. 1A)

There are at least 3 lines of evidence that suggest that urothelial cells participate in the detection of both physical and chemical stimuli. First,

Involvement of the urothelium in ‘sensing’ chemical and mechanical stimuli

A second line of evidence suggesting that urothelial cells play a role in sensory function is the expression of numerous receptors/ion channels similar to that found in both nociceptors and mechanoreceptors. Examples of neuronal “sensor molecules” (receptors/ion channels) that have been identified in urothelium include receptors for purines (P2X1–7 and P2Y1,2,4), adenosine (A1, A2a, A2b and A3), norepinephrine (α and β), acetylcholine (muscarinic and nicotinic), protease-activated receptors

ATP and purinergic receptors

Since the first report of distension-evoked ATP release from the urothelium, there has been abundant evidence supporting a role for urothelially-derived release of ATP in autocrine and paracrine signaling within the lower urinary tract. ATP is released from both the apical and basolateral urothelial surfaces in response to bladder stretch and can act on P2X2 and P2X3 urothelial receptors to stimulate stretch-induced exocytosis (Wang et al., 2005). (Fig. 1D) It has been suggested that the

Pathology-induced urothelial plasticity and effect on barrier function

Basal cells, which are thought to be precursors for other cell types, normally exhibit a low (3–6 month) turnover rate, in fact the slowest turnover of any mammalian epithelial cells (Hicks, 1975, Martin, 1972). It has been shown that neither urine-derived factors nor cyclic mechanical changes contribute to urothelial proliferation and differentiation; however accelerated proliferation can occur in pathology. For example, streptozotocin (STZ)-induced diabetes and sucrose-induced diuresis in

Clinical significance of the sensory web

Defects in urothelial sensor molecules and urothelial-cell signaling are likely to contribute to the pathophysiology of bladder diseases. For example, a number of bladder conditions (e.g., BPS/IC, spinal cord injury (SCI), chemically-induced cystitis) are associated with augmented release of urothelial-derived ATP, which is likely to result in altered sensations and changes in bladder reflexes induced by excitation of purinergic receptors on nearby sensory fibers (Birder et al., 2003, Chopra et

Acknowledgments

This work was supported by NIH grants (NIDDK R37 DK54824, R01 DK57284 and P50 DK06439).

References (120)

  • S. Du et al.

    Transient receptor potential channel A1 involved in sensory transduction of rat urinary bladder through C-fiber pathway

    Urology

    (2007)
  • M. Fovaeus et al.

    A non-nitrergic smooth muscle relaxant factor released from rat urinary bladder by muscarinic receptor stimulation

    J. Urol.

    (1999)
  • C.J. Fowler et al.

    Intravesical capsaicin for neurogenic bladder dysfunction

    Lancet.

    (1992)
  • A.T. Hanna-Mitchell et al.

    Non-neuronal acetylcholine and urinary bladder urothelium

    Life Sci.

    (2007)
  • M.A. Hass et al.

    Estrogen modulates permeability and prostaglandin levels in the rabbit urinary bladder

    Pros. Leukot. Essen. Fatty. Acids

    (2009)
  • S. Holgate

    Epithelium dysfunction in asthma

    J. Aller. Clin. Immunol.

    (2007)
  • S.T. Holgate

    The airway epithelium is central to the pathogenesis of asthma

    Allergol. Int.

    (2008)
  • M. Khera et al.

    Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury

    Neurochem. Int.

    (2004)
  • K.S. Lips et al.

    Acetylcholine and molecular components of its synthesis and release machinery in the urothelium

    Eur. Urol.

    (2007)
  • J.C. Nickel

    Interstitial cystitis — an elusive clinical target?

    J. Urol.

    (2003)
  • D. Ost et al.

    Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers

    J. Urol.

    (2002)
  • R.K. Pandita et al.

    Intravesical oxyhemoglobin initiates bladder overactivity in conscious, normal rats

    J. Urol.

    (2000)
  • C.L. Parsons et al.

    Role of surface mucin in primary antibacterial defense of bladder

    Urology

    (1977)
  • C.L. Parsons et al.

    Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis)

    J. Urol.

    (1991)
  • C.L. Parsons et al.

    The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis

    J. Urol.

    (1998)
  • A.M. Peier et al.

    A TRP channel that senses cold stimuli and menthol

    Cell

    (2002)
  • D. Robinson et al.

    The role of estrogens in female lower urinary tract dysfunction

    Urology

    (2003)
  • N.A. Salas et al.

    Receptor activated bladder and spinal ATP release in neurally intact and spinal cord injured rats

    Neurochem. Int.

    (2007)
  • Y. Shiroyanagi et al.

    Urothelial sonic hedgehog signaling plays an important role in bladder smooth muscle formation

    Differentiation

    (2007)
  • C.P. Smith et al.

    Enhanced ATP release from bladder urothelium during chronic inflammation: effect of botulinum toxin A

    Neurochem. Int.

    (2005)
  • P. Acharya et al.

    Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium

    Am. J. Physiol. Renal. Physiol.

    (2004)
  • K.E. Andersson et al.

    Nitric oxide synthase and the lower urinary tract: possible implications for physiology and pathophysiology

    Scand. J. Urol. Nephrol.

    (1995)
  • G. Anderson et al.

    Intracellular bacterial biofilm-like pods in urinary tract infections

    Science

    (2003)
  • K.E. Andersson et al.

    Urothelial effects of oral agents for overactive bladder

    Curr. Urol. Rep.

    (2008)
  • G. Apodaca

    The uroepithelium: not just a passive barrier

    Traffic

    (2004)
  • G. Apodaca et al.

    Disruption of bladder epithelium barrier function after spinal cord injury

    Am. J. Physiol. Renal. Physiol.

    (2003)
  • E.M. Balestreire et al.

    Apical EGF receptor signaling: regulation of stretch-dependent exocytosis in bladder umbrella cells

    Mol. Biol. Cell

    (2007)
  • J.A. Bassuk et al.

    Induction of urothelial cell proliferation by fibroblast growth factor-7 in RAG1-deficient mice

    Adv. Exp. Med. Biol.

    (2003)
  • J.M. Beckel et al.

    Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells

    Am. J. Physiol. Renal. Physiol.

    (2006)
  • G. Bidaux et al.

    Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement

    Endocr. Relat. Cancer.

    (2005)
  • B.K. Billips et al.

    Molecular basis of uropathogenic Escherichia coli invasion of the innate immune response in the bladder

    Infect. Immun.

    (2008)
  • L.A. Birder et al.

    Mechanisms of disease: involvement of the urothelium in bladder dysfunction

    Clin. Prac.

    (2007)
  • L.A. Birder et al.

    Adrenergic and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder

    Am. J. Physiol.

    (1998)
  • L.A. Birder et al.

    Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells

    PNAS

    (2001)
  • L.A. Birder et al.

    Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1

    Nat. Neurosci.

    (2002)
  • L.A. Birder et al.

    Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium

    Am. J. Physiol. Renal. Physiol.

    (2003)
  • L. Birder et al.

    Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12, 13-didecanoate contributes to altered bladder reflexes in the rat

    J. Pharma. Exp. Ther.

    (2007)
  • Y. Bosse et al.

    Airway wall remodeling in asthma: from the epithelial layer to the adventitia

    Curr. Allergy Asthma Rep.

    (2008)
  • A.F. Brading et al.

    Mechanisms of disease: specialized interstitial cells of the urothelium: an assessment of current knowledge

    Nature. Clin. Prac. Urol.

    (2005)
  • C.M. Brady 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)
  • Cited by (89)

    • Voluntary versus reflex micturition control

      2023, Neuro-Urology Research: A Comprehensive Overview
    • Vesicular polyamine transporter as a novel player in amine-mediated chemical transmission

      2020, Biochimica et Biophysica Acta - Biomembranes
      Citation Excerpt :

      The recently identified PQ transporter in Arabidopsis, PQ tolerance-conferring protein, belongs to the L-type amino acid transporter family and is structurally unrelated to VPAT (Table 2) [120]. Recent evidence indicates that bladder urothelial cells exhibit neuron-like properties that may contribute to bladder functions [121]. Functional V-ATPase is present in bladder tubulovesicles, and is involved in the regulation of urinary pH [122].

    • Elevated release of inflammatory but not sensory mediators from the urothelium is maintained following epirubicin treatment

      2019, European Journal of Pharmacology
      Citation Excerpt :

      The urothelium is in direct contact with the cytotoxic agents during intravesical treatment. While the urothelium serves as a distensible barrier to protect the underlying tissues from the potentially harmful contents of the urine, it also responds to bladder filling, by releasing a number of chemical transmitters including ATP (Burnstock, 2011a), acetylcholine (Birder, 2010), prostaglandin E2 (PGE2) (Tanaka et al., 2011) and nitric oxide (NO) (Winder et al., 2017). These transmitters are involved in regulating sensory mechanisms and bladder contraction playing essential roles in maintaining normal bladder function.

    • The aging bladder insights from animal models

      2018, Asian Journal of Urology
      Citation Excerpt :

      The prevalence of both storage and voiding lower urinary tract symptoms (LUTS) increases significantly over the age of 65 years in patients of both sexes [1]. It is well recognized that overactive bladder (OAB) symptom syndrome and urodynamic evidence of bladder overactivity which is seen in a proportion of these patients increases in both sexes with increasing age as does detrusor underactivity and indeed both can co-exist in the same patient [2]. Furthermore there is a clearly increasing prevalence of bladder outflow obstruction in the aging male population.

    • New Frontiers of Basic Science Research in Neurogenic Lower Urinary Tract Dysfunction

      2017, Urologic Clinics of North America
      Citation Excerpt :

      Desensitization of C-fiber afferent pathways by capsaicin pretreatment also reduces DSD in chronic SCI rats.86 Furthermore, it has also been shown in the cat that C-fiber bladder afferents are responsible for cold-induced bladder reflexes via TRPM8 receptors.29,87 Chronic SCI in humans also causes the emergence of an unusual bladder reflex that is elicited by infusion of cold water into the bladder, which is blocked by intravesical capsaicin treatment.88–90

    View all citing articles on Scopus
    View full text