title: 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.
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montalbetti
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Anna C
authors.initials: AC
authors.lastname: Rued
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Clayton
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Wily G
authors.initials: WG
authors.lastname: Ruiz
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sheldon I
authors.initials: SI
authors.lastname: Bastacky
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: H Sandeep
authors.initials: HS
authors.lastname: Prakasam
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Amity F
authors.initials: AF
authors.lastname: Eaton
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: F Aura
authors.initials: FA
authors.lastname: Kullmann
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Apodaca
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and mdc4@pitt.edu.
authors.forename: Marcelo D
authors.initials: MD
authors.lastname: Carattino
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000502:physiology*; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D003556:Cystitis / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology
chemical_list: D057167:Claudins; C491874:Cldn2 protein, rat
keywords: claudin-2; cystitis; interstitial cystitis/painful bladder syndrome; paracellular permeability; tight junctions; urinary bladder