MP60-20 ROLE OF SHH PATHWAY IN URINARY CONTINENCE AND ITS IMPACT ON CELLULAR FATE IN MOUSE URETHRA

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP60-20 ROLE OF SHH PATHWAY IN URINARY CONTINENCE AND ITS IMPACT ON CELLULAR FATE IN MOUSE URETHRA Walid Farhat, Priyank Yadav, Marcela Ambrogi, Audrey Spiegelhoff, Chad Vezina, and Kimberly Keil Stietz Walid FarhatWalid Farhat More articles by this author , Priyank YadavPriyank Yadav More articles by this author , Marcela AmbrogiMarcela Ambrogi More articles by this author , Audrey SpiegelhoffAudrey Spiegelhoff More articles by this author , Chad VezinaChad Vezina More articles by this author , and Kimberly Keil StietzKimberly Keil Stietz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sonic hedgehog (Shh) signaling is critical in many developing organs and subject to disruption through gene-environment interactions. Urinary continence is dependent on appropriate development of bladder neck and urethra driven by epithelial-mesenchymal interactions mediated in part by SHH. To further understand the impact of Shh pathway disruption on lower urinary tract and continence, we examined voiding physiology and histology in compound mutant GLI family zinc finger Gli2+/−; Gli3Δ699/+ mice, which have hypomorphic hedgehog signaling. METHODS: Voiding physiology was tested in young adult female mice (n=5-8/genotype) using void spot assay, uroflowmetry and ex vivo bladder bath assays. Urethra and bladder (n=3/genotype) were collected for immunostaining using antibodies against smooth muscle alpha actin to visualize urethral smooth muscle thickness, or uroplakin, transformation related protein 63, and keratin 5 (combinatorial staining resolves basal, intermediate and luminal epithelial cells). RESULTS: Gli2+/−; Gli3Δ699/+ female mice void more urine spots, void more spots of smaller diameter and void a greater percentage of urine in the cage center than wild type mice. Voids from Gli2+/−; Gli3Δ699/+ mice, measured by uroflowmetry, weigh less (indicating smaller volume) and are shorter in duration than wild type mice. Gli2+/−; Gli3Δ699/+ female mouse bladders, isolated in ex vivo bath preparations, are less responsive to electrical field stimulation and potassium chloride than bladders from wild type mice. Our results are consistent with detrusor under activity and potential stress incontinence in Gli2+/−; Gli3Δ699/+ female mice. In search for a physiological mechanism, we conducted histological analysis to reveal a clear anatomic boundary between wild type mouse bladder neck and urethra. Umbrella shaped uroplakin+ cells populate the bladder neck and cuboidal shaped uroplakin- superficial cells populate the urethra. The bladder neck epithelium of Gli2+/−; Gli3Δ699/+ mice does not appreciably differ from wild type, but urethral epithelial cells are uroplakin+, suggesting possible segmental deficits during urethral development that may account in part for incontinence in Gli2+/−; Gli3Δ699/+ mice. CONCLUSIONS: Our data suggest that establishing continent voiding function in mice is dependent on appropriate urethra epithelial cell fate. Future work to understand mechanisms underlying decreased bladder contractile properties, and urethral cell fate will enhance understanding of the continence mechanism. Source of Funding: DK104310 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e851 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Walid Farhat More articles by this author Priyank Yadav More articles by this author Marcela Ambrogi More articles by this author Audrey Spiegelhoff More articles by this author Chad Vezina More articles by this author Kimberly Keil Stietz More articles by this author Expand All Advertisement PDF downloadLoading ...