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Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1

Pain is the significant presenting symptom in Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS). Activation of urothelial protease activated receptor 4 (PAR4) causes pain through release of urothelial macrophage migration inhibitory factor (MIF). High Mobility Group Box-1 (HMGB1), a chromatin-...

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Autores principales: Kouzoukas, Dimitrios E., Ma, Fei, Meyer-Siegler, Katherine L., Westlund, Karin N., Hunt, David E., Vera, Pedro L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806866/
https://www.ncbi.nlm.nih.gov/pubmed/27010488
http://dx.doi.org/10.1371/journal.pone.0152055
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author Kouzoukas, Dimitrios E.
Ma, Fei
Meyer-Siegler, Katherine L.
Westlund, Karin N.
Hunt, David E.
Vera, Pedro L.
author_facet Kouzoukas, Dimitrios E.
Ma, Fei
Meyer-Siegler, Katherine L.
Westlund, Karin N.
Hunt, David E.
Vera, Pedro L.
author_sort Kouzoukas, Dimitrios E.
collection PubMed
description Pain is the significant presenting symptom in Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS). Activation of urothelial protease activated receptor 4 (PAR4) causes pain through release of urothelial macrophage migration inhibitory factor (MIF). High Mobility Group Box-1 (HMGB1), a chromatin-binding protein, mediates bladder pain (but not inflammation) in an experimental model (cyclophosphamide) of cystitis. To determine if PAR4-induced bladder hypersensitivity depends on HMGB1 downstream, we tested whether: 1) bladder PAR4 stimulation affected urothelial HMGB1 release; 2) blocking MIF inhibited urothelial HMGB1 release; and 3) blocking HMGB1 prevented PAR4-induced bladder hypersensitivity. HMGB1 release was examined in immortalized human urothelial cultures (UROtsa) exposed to PAR4-activating peptide (PAR4-AP; 100 μM; 2 hours) or scrambled control peptide. Female C57BL/6 mice, pretreated with a HMGB1 inhibitor (glycyrrhizin: 50 mg/kg; ip) or vehicle, received intravesical PAR4-AP or a control peptide (100 μM; 1 hour) to determine 1) HMGB1 levels at 1 hour in the intravesical fluid (released HMGB1) and urothelium, and 2) abdominal hypersensitivity to von Frey filament stimulation 24 hours later. We also tested mice pretreated with a MIF blocker (ISO-1: 20 mg/kg; ip) to determine whether MIF mediated PAR4-induced urothelial HMGB1 release. PAR4-AP triggered HMGB1 release from human (in vitro) and mice (in vivo) urothelial cells. Intravesical PAR4 activation elicited abdominal hypersensitivity in mice that was prevented by blocking HMGB1. MIF inhibition prevented PAR4-mediated HMGB1 release from mouse urothelium. Urothelial MIF and HGMB1 represent novel targets for therapeutic intervention in bladder pain conditions.
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spelling pubmed-48068662016-03-25 Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1 Kouzoukas, Dimitrios E. Ma, Fei Meyer-Siegler, Katherine L. Westlund, Karin N. Hunt, David E. Vera, Pedro L. PLoS One Research Article Pain is the significant presenting symptom in Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS). Activation of urothelial protease activated receptor 4 (PAR4) causes pain through release of urothelial macrophage migration inhibitory factor (MIF). High Mobility Group Box-1 (HMGB1), a chromatin-binding protein, mediates bladder pain (but not inflammation) in an experimental model (cyclophosphamide) of cystitis. To determine if PAR4-induced bladder hypersensitivity depends on HMGB1 downstream, we tested whether: 1) bladder PAR4 stimulation affected urothelial HMGB1 release; 2) blocking MIF inhibited urothelial HMGB1 release; and 3) blocking HMGB1 prevented PAR4-induced bladder hypersensitivity. HMGB1 release was examined in immortalized human urothelial cultures (UROtsa) exposed to PAR4-activating peptide (PAR4-AP; 100 μM; 2 hours) or scrambled control peptide. Female C57BL/6 mice, pretreated with a HMGB1 inhibitor (glycyrrhizin: 50 mg/kg; ip) or vehicle, received intravesical PAR4-AP or a control peptide (100 μM; 1 hour) to determine 1) HMGB1 levels at 1 hour in the intravesical fluid (released HMGB1) and urothelium, and 2) abdominal hypersensitivity to von Frey filament stimulation 24 hours later. We also tested mice pretreated with a MIF blocker (ISO-1: 20 mg/kg; ip) to determine whether MIF mediated PAR4-induced urothelial HMGB1 release. PAR4-AP triggered HMGB1 release from human (in vitro) and mice (in vivo) urothelial cells. Intravesical PAR4 activation elicited abdominal hypersensitivity in mice that was prevented by blocking HMGB1. MIF inhibition prevented PAR4-mediated HMGB1 release from mouse urothelium. Urothelial MIF and HGMB1 represent novel targets for therapeutic intervention in bladder pain conditions. Public Library of Science 2016-03-24 /pmc/articles/PMC4806866/ /pubmed/27010488 http://dx.doi.org/10.1371/journal.pone.0152055 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Kouzoukas, Dimitrios E.
Ma, Fei
Meyer-Siegler, Katherine L.
Westlund, Karin N.
Hunt, David E.
Vera, Pedro L.
Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title_full Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title_fullStr Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title_full_unstemmed Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title_short Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1
title_sort protease-activated receptor 4 induces bladder pain through high mobility group box-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806866/
https://www.ncbi.nlm.nih.gov/pubmed/27010488
http://dx.doi.org/10.1371/journal.pone.0152055
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