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Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice

Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Ca(v)3.2 T-type Ca(2+) channel activity by H(2)S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/...

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Autores principales: Hiramoto, Shiori, Tsubota, Maho, Yamaguchi, Kaoru, Okazaki, Kyoko, Sakaegi, Aya, Toriyama, Yuki, Tanaka, Junichi, Sekiguchi, Fumiko, Ishikura, Hiroyasu, Wake, Hidenori, Nishibori, Masahiro, Nguyen, Huy Du, Okada, Takuya, Toyooka, Naoki, Kawabata, Atsufumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463894/
https://www.ncbi.nlm.nih.gov/pubmed/32707767
http://dx.doi.org/10.3390/cells9081748
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author Hiramoto, Shiori
Tsubota, Maho
Yamaguchi, Kaoru
Okazaki, Kyoko
Sakaegi, Aya
Toriyama, Yuki
Tanaka, Junichi
Sekiguchi, Fumiko
Ishikura, Hiroyasu
Wake, Hidenori
Nishibori, Masahiro
Nguyen, Huy Du
Okada, Takuya
Toyooka, Naoki
Kawabata, Atsufumi
author_facet Hiramoto, Shiori
Tsubota, Maho
Yamaguchi, Kaoru
Okazaki, Kyoko
Sakaegi, Aya
Toriyama, Yuki
Tanaka, Junichi
Sekiguchi, Fumiko
Ishikura, Hiroyasu
Wake, Hidenori
Nishibori, Masahiro
Nguyen, Huy Du
Okada, Takuya
Toyooka, Naoki
Kawabata, Atsufumi
author_sort Hiramoto, Shiori
collection PubMed
description Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Ca(v)3.2 T-type Ca(2+) channel activity by H(2)S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H(2)S/Ca(v)3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca(2+) channels or CSE, and genetic deletion of Ca(v)3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X(4)/P2X(7) receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X(7)/P2X(4), and caused HMGB1 release via P2X(7) in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent H(2)S-targeted Ca(v)3.2-dependent nociceptor excitation, resulting in bladder pain.
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spelling pubmed-74638942020-09-04 Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice Hiramoto, Shiori Tsubota, Maho Yamaguchi, Kaoru Okazaki, Kyoko Sakaegi, Aya Toriyama, Yuki Tanaka, Junichi Sekiguchi, Fumiko Ishikura, Hiroyasu Wake, Hidenori Nishibori, Masahiro Nguyen, Huy Du Okada, Takuya Toyooka, Naoki Kawabata, Atsufumi Cells Article Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Ca(v)3.2 T-type Ca(2+) channel activity by H(2)S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H(2)S/Ca(v)3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca(2+) channels or CSE, and genetic deletion of Ca(v)3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X(4)/P2X(7) receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X(7)/P2X(4), and caused HMGB1 release via P2X(7) in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent H(2)S-targeted Ca(v)3.2-dependent nociceptor excitation, resulting in bladder pain. MDPI 2020-07-22 /pmc/articles/PMC7463894/ /pubmed/32707767 http://dx.doi.org/10.3390/cells9081748 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hiramoto, Shiori
Tsubota, Maho
Yamaguchi, Kaoru
Okazaki, Kyoko
Sakaegi, Aya
Toriyama, Yuki
Tanaka, Junichi
Sekiguchi, Fumiko
Ishikura, Hiroyasu
Wake, Hidenori
Nishibori, Masahiro
Nguyen, Huy Du
Okada, Takuya
Toyooka, Naoki
Kawabata, Atsufumi
Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title_full Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title_fullStr Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title_full_unstemmed Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title_short Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H(2)S/Ca(v)3.2 Signaling in Mice
title_sort cystitis-related bladder pain involves atp-dependent hmgb1 release from macrophages and its downstream h(2)s/ca(v)3.2 signaling in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463894/
https://www.ncbi.nlm.nih.gov/pubmed/32707767
http://dx.doi.org/10.3390/cells9081748
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