Increased urothelial paracellular transport promotes cystitis

Abstract

Changes in the urothelial barrier are observed in patients with cystitis, but whether this leads to inflammation or occurs in response to it is currently unknown. To determine whether urothelial barrier dysfunction is sufficient to promote cystitis, we employed in situ adenoviral transduction to selectively overexpress the pore-forming tight junction-associated protein claudin-2 (CLDN-2). As expected, the expression of CLDN-2 in the umbrella cells increased the permeability of the paracellular route toward ions, but not to large organic molecules. In vivo studies of bladder function revealed higher intravesical basal pressures, reduced compliance, and increased voiding frequency in rats transduced with CLDN-2 vs. controls transduced with green fluorescent protein. While the integrity of the urothelial barrier was preserved in the rats transduced with CLDN-2, we found that the expression of this protein in the umbrella cells initiated an inflammatory process in the urinary bladder characterized by edema and the presence of a lymphocytic infiltrate. Taken together, these results are consistent with the notion that urothelial barrier dysfunction may be sufficient to trigger bladder inflammation and to alter bladder function.

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.…”

The Prospect of Cluster Analysis’ Use to Obtain the New Scientific Results at the Example of Urotheliocytes’ Study in Experimental Diabetic Cystopathy

“…According to N. Montalbetti et al such urothelial paracellular transport of substances is possible even without damage to the urothelial barrier. [15].…”

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

“…Although the main role of bladder urothelium is thought to provide a barrier which is impermeable to all urinary solutes, reduced urothelial barrier function has been observed in patients with IC/BPS [40,41]. A recent study in rats has shown altered expression and function of paracellular tight junctions in the urothelium may trigger bladder inflammation and promote cystitis [42].…”

“…Other urothelial associated proteins also contribute to the permeability barrier. These include the uroplakins that form a covering over the urothelial luminal surface [51] and the tight junction proteins that bind the urothelial cells together [42]. In patients with IC/BPS, there is an absence of the tight junction protein zona occludens-1 (ZO-1), and also there are deficiencies in the expression of uroplakin and E-cadherin [40].…”