Nitric oxide in bladder neural-epithelial signaling

Summary

Principal Investigator: L Birder
Abstract: Recent studies have revealed that the urinary bladder (UB) epithelium (urothelium) is involved in sensory mechanisms and can release chemical mediators (nitric oxide; ATP). Localization of afferent nerves next to the urothelium suggests these cells may be targets for transmitters released from bladder nerves or that chemicals released by urothelial cells may alter afferent excitability. Both afferent nerves and urothelial cells exhibit common properties including the expression of certain receptors and channels. For example, demonstration of vanilloid receptors (VR1) in urothelial cells sensitive to capsaicin and protons suggests that VRI in non-neuronal cells may have a role in sensory mechanisms. Moreover, the properties of afferents and urothelial cells are plastic and can be changed by pathology. Our data suggest that altered production of mediators following injury/inflammation may influence afferent excitability and urothelial function, by increasing permeability to noxious substances. This suggests that the epithelium is involved in intercellular signaling and that neural-epithelial interactions can play a critical role in the regulation of afferent excitability. Using a multidisciplinary approach involving molecular biology, transmitter release, imaging techniques using photodiode arrays and in vivo monitoring of afferent and reflex bladder activity, our goals are to further characterize the properties of urothelial cells and determine the signaling mechanisms responsible for cell-cell (neural-epithelial, inter-epithelial) interactions. Aim #1 will evaluate the intracellular signaling mechanisms underlying the neuron-like properties of urothelial cells. Although urothelial cells and sensory neurons exhibit common properties, little is known about mechanisms involved in urothelial signaling and how they might influence bladder function. This aim will examine the mechanisms involved in chemo-and mechanical signaling in urothelium. Aim #2 will evaluate the chemical mechanisms involved in cell-cell signaling. This aim will explore the transmitter/signaling mechanisms involved in neural-epithelial interactions and the impact on signaling in the urothelium. Aim #3 will evaluate the effect of pathology on urothelial properties/signaling. This aim will examine the impact of inflammation and injury on signaling pathways in urothelial cells and on communication with other cell types. Elucidation of mechanisms impacting on urothelial function may provide insights into the pathology of bladder dysfunction.
Funding Period: 1999-02-15 - 2006-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Sophisticated models and methods for studying neurogenic bladder dysfunction
    Anthony Kanai
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Neurourol Urodyn 30:658-67. 2011
  2. pmc Is the urothelium intelligent?
    L A Birder
    Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA
    Neurourol Urodyn 29:598-602. 2010
  3. pmc Functional TRP and ASIC-like channels in cultured urothelial cells from the rat
    F Aura Kullmann
    Dept of Pharmacology and Chemical Biology, Univ of Pittsburgh School of Medicine, E 1340 Biomedical Science Tower, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 296:F892-901. 2009
  4. pmc Expression and function of rat urothelial P2Y receptors
    Bikramjit Chopra
    A1207 Scaife Hall, Dept of Medicine, Univ of Pittsburgh, 3550 Terrace St, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 294:F821-9. 2008
  5. pmc TRPs in bladder diseases
    Lori A Birder
    University of Pittsburgh School of Medicine, Department of Medicine and Pharmacology, A 1207 Scaife Hall, Pittsburgh, PA 15261, USA
    Biochim Biophys Acta 1772:879-84. 2007
  6. pmc Non-neuronal acetylcholine and urinary bladder urothelium
    Ann T Hanna-Mitchell
    University of Pittsburgh School of Medicine Department of Medicine, Pittsburgh, PA 15261, USA
    Life Sci 80:2298-302. 2007
  7. pmc Role of urothelial nerve growth factor in human bladder function
    Lori A Birder
    Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Neurourol Urodyn 26:405-9. 2007
  8. pmc Mechanisms of disease: involvement of the urothelium in bladder dysfunction
    Lori A Birder
    Department of Medicine, Renal Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Nat Clin Pract Urol 4:46-54. 2007
  9. pmc Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists
    A Kanai
    Department of Medicine, University of Pittsburgh School of Medicine, A1224 Scaife Hall, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 292:F1065-72. 2007
  10. ncbi Urinary bladder urothelium: molecular sensors of chemical/thermal/mechanical stimuli
    Lori A Birder
    University of Pittsburgh School of Medicine, A 1207 Scaife Hall, Department of Medicine, Pittsburgh, PA 15261, United States
    Vascul Pharmacol 45:221-6. 2006

Scientific Experts

  • L Birder
  • ANTHONY JOHN KANAI
  • Jonathan M Beckel
  • Bikramjit Chopra
  • Ann T Hanna-Mitchell
  • F Aura Kullmann
  • Anthony P D W Ford
  • Stacey R Barrick
  • William C de Groat
  • Edward C Y Wang
  • W C de Groat
  • M A Shah
  • Joel Gever
  • Stephanie Barbadora
  • Debra A Cockayne
  • Stacey Barrick
  • Susan Meyers
  • Mark L Zeidel
  • Elena M Balestreire
  • Gerard Apodaca
  • Maximilian von Bodungen
  • Jey Myung Lee
  • Wily G Ruiz

Detail Information

Publications15

  1. ncbi Sophisticated models and methods for studying neurogenic bladder dysfunction
    Anthony Kanai
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Neurourol Urodyn 30:658-67. 2011
    ..To describe how the use of new and established animal models and methods can generate vital and far reaching experimental data in the study of mechanism underlying neurogenic bladder overactivity...
  2. pmc Is the urothelium intelligent?
    L A Birder
    Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA
    Neurourol Urodyn 29:598-602. 2010
    ..The advantage of this approach is that input-output functions can be mathematically formulated, and the importance of different components contributing to abnormal urinary tract function can be calculated...
  3. pmc Functional TRP and ASIC-like channels in cultured urothelial cells from the rat
    F Aura Kullmann
    Dept of Pharmacology and Chemical Biology, Univ of Pittsburgh School of Medicine, E 1340 Biomedical Science Tower, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 296:F892-901. 2009
    ..These "neuron-like" properties might be involved in transmitter release, such as ATP, that can act on afferent nerves or smooth muscle to modulate their responses to different stimuli...
  4. pmc Expression and function of rat urothelial P2Y receptors
    Bikramjit Chopra
    A1207 Scaife Hall, Dept of Medicine, Univ of Pittsburgh, 3550 Terrace St, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 294:F821-9. 2008
    ..This could lead to the release of bioactive mediators such as additional ATP, nitric oxide, and acetylcholine, which can modulate the micturition reflex by acting on suburothelial myofibroblasts and/or pelvic afferent fibers...
  5. pmc TRPs in bladder diseases
    Lori A Birder
    University of Pittsburgh School of Medicine, Department of Medicine and Pharmacology, A 1207 Scaife Hall, Pittsburgh, PA 15261, USA
    Biochim Biophys Acta 1772:879-84. 2007
    ..I. Nagy, P. Santha, G. Jansco, L. Urban, The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology, European Journal of Pharmacology 500, (2004) 351-369.]...
  6. pmc Non-neuronal acetylcholine and urinary bladder urothelium
    Ann T Hanna-Mitchell
    University of Pittsburgh School of Medicine Department of Medicine, Pittsburgh, PA 15261, USA
    Life Sci 80:2298-302. 2007
    ..These observations indicate that acetylcholine release from urothelial cells is mediated by different mechanisms than those such as vesicular storage and exocytosis that underlie the release of neurotransmitters from nerves...
  7. pmc Role of urothelial nerve growth factor in human bladder function
    Lori A Birder
    Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Neurourol Urodyn 26:405-9. 2007
    ..To test whether nerve growth factor (NGF) concentration in human bladder urothelium/suburothelium is related to detrusor overactivity (DO), bladder sensation, detrusor contractility, or other aspects of lower urinary tract function...
  8. pmc Mechanisms of disease: involvement of the urothelium in bladder dysfunction
    Lori A Birder
    Department of Medicine, Renal Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Nat Clin Pract Urol 4:46-54. 2007
    ..Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction...
  9. pmc Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists
    A Kanai
    Department of Medicine, University of Pittsburgh School of Medicine, A1224 Scaife Hall, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 292:F1065-72. 2007
    ..Activity is enhanced by stretch or carbachol and this enhancement is blocked by atropine. It is hypothesized that acetylcholine is released from the urothelium during bladder filling to enhance spontaneous activity...
  10. ncbi Urinary bladder urothelium: molecular sensors of chemical/thermal/mechanical stimuli
    Lori A Birder
    University of Pittsburgh School of Medicine, A 1207 Scaife Hall, Department of Medicine, Pittsburgh, PA 15261, United States
    Vascul Pharmacol 45:221-6. 2006
    ..These and other findings highlight the functional importance of the urinary bladder urothelium and suggest that perturbations in urothelial targets and/or cell-cell interactions may lead to a number of urinary tract abnormalities...
  11. ncbi Role of the urothelium in urinary bladder dysfunction following spinal cord injury
    Lori A Birder
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Prog Brain Res 152:135-46. 2006
    ..Taken together, these and other findings discussed in this chapter suggest a sensory function for the urothelium and that alterations in urothelial properties may contribute to afferent abnormalities following spinal cord injury...
  12. pmc Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells
    Jonathan M Beckel
    Dept of Pharmacology, Univ of Pittsburgh School of Medicine, A1220 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 290:F103-10. 2006
    ..These results are the first indication that stimulation of nonneuronal nicotinic receptors in the bladder can affect micturition...
  13. pmc ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells
    Edward C Y Wang
    Renal Electrolyte Division and Laboratory of Epithelial Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Clin Invest 115:2412-22. 2005
    ....
  14. ncbi More than just a barrier: urothelium as a drug target for urinary bladder pain
    Lori A Birder
    Univ of Pittsburgh School of Medicine, Dept of Medicine, A 1207 Scaife Hall, Pittsburgh, PA 15261, USA
    Am J Physiol Renal Physiol 289:F489-95. 2005
    ..Taken together, these and other findings highlighted in this review suggest a sensory function for the urothelium. Elucidation of mechanisms impacting on urothelial function may provide insights into the pathology of bladder dysfunction...
  15. pmc Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium
    Bikramjit Chopra
    A1207 Scaife Hall, Department of Medicine Renal Division, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA
    J Physiol 562:859-71. 2005
    ..These studies demonstrate that urothelial expression of bradykinin receptors is plastic and is altered by pathology...