Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight junction (TJ)-associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain.

Purinergic P2X7 receptors as therapeutic targets in interstitial cystitis/bladder pain syndrome; key role of ATP signaling in inflammation

“…Similar to the reports in human IC/BPS, a significant elevation in stretch-evoked ATP release has been demonstrated in a feline model of IC/BPS [111] and in cyclophosphamide-induced chronic (hemorrhagic) bladder inflammation in rats [129]. The high level of ATP and other urinary contents may diffuse through the leaky urothelium to sensitize bladder afferents, causing pain sensation and stimulating voiding, which are the typical symptoms of IC/BPS [130].…”

Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions

“…Metabolic-cage studies in untreated, aged (>25 months) versus young adult Fischer 344 rats revealed decreases in voiding frequency ( Figure 1A ) and increases in the intervoid interval ( Figure 1B ), as well as voided volume ( Figure 1C ), in aged rats. Also, aged rats demonstrated decreased von Frey sensitivity ( 14 , 15 ) to tactile (mechanical) stimuli, both abdominal (visceral; Figure 1D ) and cutaneous (hind paw; Figure 1E ). The von Frey test is a noninvasive behavioral method that uses a series of calibrated von Frey filaments to assess the sensitivity to mechanical stimuli (i.e., response to pressure stimuli) at various anatomical locations.…”

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

“…Montalbetti et al. showed that, in rats, increased urothelial permeability caused by disrupted urothelial tight junctions resulted in bladder afferent nerve hyperexcitability and upstream central nerve sensitization with few inflammatory changes, and without altering epithelial quantity or umbrella cell polarity/differentiation 130,131 . In contrast, emerging evidence has suggested a potential connection between bladder/pelvic hypersensitivity and psychological/physiological stress, involving functional alteration of the CNS, in humans.…”