Mechanisms of disease: involvement of the urothelium in bladder dysfunction

Abstract

Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions and solutes, a number of novel properties have been recently attributed to urothelial cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e. the ability to express a number of sensor molecules or respond to thermal, mechanical and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests that urothelial cells could be targets for neurotransmitters released from bladder nerves or that chemicals released by urothelial cells could alter afferent nerve excitability. Taken together, these and other findings highlighted in this article suggest a sensory function for the urothelium. Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction.

Figure 1

Hypothetical model that depicts possible interactions between bladder afferent and efferent nerves, urothelial cells, smooth muscle and myofibroblasts. Stimulation of receptors and channels on urothelial cells can release mediators that target bladder nerves and other cell types; urothelial cells can also be targets for neurotransmitters released from nerves or other cell types. Urothelial cells can be activated by either autocrine (i.e. autoregulation) or paracrine (release from nearby nerves or other cells) mechanisms. Abbreviations: ACh, acetylcholine; AdR, adrenergic receptor; BR, bradykinin receptor; H⁺, proton; MR, muscarinic receptor; NE, norepinephrine; NGF, nerve growth factor; NR, neurokinin receptor; NicR, nicotinic receptor; NO, nitric oxide; P2R, purinergic 2 receptor unidentified subtype; P2X and P2Y, purinergic receptors; PG, prostaglandin; SP, substance P; Trk-A, receptor tyrosine kinase A, high affinity receptor for nerve growth factor; TRPs, transient receptor potential channels.

Figure 2

Expression of transient receptor potential cation channel subfamily V member 1 (TRPV1) in urothelial cells of the rat urinary bladder. (A) Confocal image of bladder urothelium in bladder whole mounts that have been immunofluorescently labeled for TRPV1 (cyanine 3, red) and cytokeratin 17 (fluorescein, green), a marker for basal urothelial cells. Scale bar 15 μm. (B) Enlarged image of basal cells depicting TRPV1 (cyanine 3, red) and cytokeratin (fluorescein, green) immunoreactivity. Scale bar 5 μm.