Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis

Michael C. Chen, Christopher S. Mudge, David J. Klumpp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that shares similarities with Crohn's disease and psoriasis. IC, often regarded as a neurogenic cystitis, is associated with urothelial lesions that likely compromise the bladder permeability barrier and thereby contribute to patient morbidity. Here, we use a murine model of neurogenic cystitis to investigate the mechanism of urothelial lesion formation and find that urothelial apoptosis induces formation of lesions. Lesions formed in wild-type mice but not in mice deficient in TNF, TNF receptors, or mast cells. In urothelial cultures, only siRNAs targeting TNFR1, but not TNFR2, blocked TNF-induced apoptosis, indicating a primary role for TNFR1. Trans-epithelial resistance, a measure of bladder barrier function, decreased during neurogenic cystitis in wild-type and TNFR2-/- mice but was stabilized in TNF-/- mice. Anti-TNF antibodies both altered bladder mast cell localization and stabilized barrier function. Based on these findings, we conclude that mast cell activation and release of TNF drive urothelial apoptosis and lesion formation in a murine neurogenic cystitis model, and we hypothesize that anti-TNF therapy may stabilize bladder barrier function in IC patients.

Original languageEnglish (US)
Pages (from-to)F741-F749
JournalAmerican Journal of Physiology - Renal Physiology
Volume291
Issue number4
DOIs
StatePublished - 2006

Keywords

  • Apoptosis
  • Bladder barrier function
  • Interstitial cystitis
  • Urothelium

ASJC Scopus subject areas

  • Physiology
  • Urology

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