36 A PUTATIVE MECHANISM FOR PANNEXIN 1 INVOLVEMENT IN BLADDER DYSFUNCTION IN AN ANIMAL MODEL OF MULTIPLE SCLEROSIS

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research (1)1 Apr 201336 A PUTATIVE MECHANISM FOR PANNEXIN 1 INVOLVEMENT IN BLADDER DYSFUNCTION IN AN ANIMAL MODEL OF MULTIPLE SCLEROSIS Hiromitsu Negoro, Sarah Lutz, Eliana Scemes, and Sylvia Suadicani Hiromitsu NegoroHiromitsu Negoro Bronx, NY More articles by this author , Sarah LutzSarah Lutz Bronx, NY More articles by this author , Eliana ScemesEliana Scemes Bronx, NY More articles by this author , and Sylvia SuadicaniSylvia Suadicani Bronx, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1411AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Neurogenic bladder is common in patients with Multiple Sclerosis (MS), but little is known about the underlying molecular mechanisms. In this study we show that in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS, genetic deletion of pannexin 1 (Panx1) ameliorates micturition dysfunction and prevents upregulation of interleukin 1 beta (IL-1β) and connexin 43 (Cx43; gap junction protein) in bladder mucosa of EAE mice. In other systems, Panx1 has been implicated in caspase 1 (Casp1) activation for IL-1β maturation, and IL-1β has been shown to modulate Cx43 expression. We here investigate whether this signaling axis also operates in bladder mucosa. METHODS 1) EAE was induced in Panx1+/+ and Panx1−/− mice by immunization with MOG35-55 peptide and neurological deficits scored. Micturition pattern was measured in chronic phase (35-42 days-post immunization) and bladder tissues harvested for qPCR and immunoblotting. 2) hTERT-immortalized human bladder urothelial cell (TRT-HU) cultures were stimulated with IL-1β in presence and absence of SB20358 (p38 MAPK inhibitor), U0126 (MEK inhibitor) or mefloquine (MFQ, Panx1 blocker), and harvested for qPCR and immunoblotting. Cx43 function was evaluated by Lucifer yellow dye-transfer. RESULTS Cx43 mRNA/protein and IL-1β mRNA expression was significantly higher in bladder mucosa of Panx1+/+ EAE compared to naive mice. This was not observed in Panx1−/− mice, which also displayed lesser bladder dysfunction than Panx1+/+ despite having similar neurological deficits in chronic phase. In TRT-HU cells, IL-1β stimulation increased Cx43 expression and dye-transfer, increased p38 MAPK but not ERK1/2 phosphorylation, and SB20358 but not U0126 prevented IL-1β-induced Cx43 upregulation. IL-1β also increased IL-1β, interleukin receptor type 1 (IL-1R-1), Panx1 and Casp1 mRNA expression. MFQ treatment inhibited these responses to IL-1β. CONCLUSIONS Mechanisms for micturition dysfunction in EAE mice may include a positive feedback loop between Panx1 and IL-1β signaling via Casp1 and IL-1R-1 that modulates Cx43 expression in urothelial cells. Inhibition of this loop may provide a new target for treatment and prevention of neurogenic bladder in MS patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e14 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiromitsu Negoro Bronx, NY More articles by this author Sarah Lutz Bronx, NY More articles by this author Eliana Scemes Bronx, NY More articles by this author Sylvia Suadicani Bronx, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...