Urothelial signaling
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).
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