Genomes and Genes
Nitric oxide in bladder neural-epithelial signaling
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
- Sophisticated models and methods for studying neurogenic bladder dysfunctionAnthony 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...
- 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...
- Functional TRP and ASIC-like channels in cultured urothelial cells from the ratF 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...
- Expression and function of rat urothelial P2Y receptorsBikramjit 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...
- TRPs in bladder diseasesLori 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.]...
- Non-neuronal acetylcholine and urinary bladder urotheliumAnn 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...
- Role of urothelial nerve growth factor in human bladder functionLori 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...
- Mechanisms of disease: involvement of the urothelium in bladder dysfunctionLori 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...
- Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonistsA 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...
- Urinary bladder urothelium: molecular sensors of chemical/thermal/mechanical stimuliLori 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...
- Role of the urothelium in urinary bladder dysfunction following spinal cord injuryLori 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...
- Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cellsJonathan 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...
- ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cellsEdward 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....
- More than just a barrier: urothelium as a drug target for urinary bladder painLori 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...
- Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urotheliumBikramjit 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...