{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:28:15Z","timestamp":1790422095184,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T00:00:00Z","timestamp":1595376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K09046"],"award-info":[{"award-number":["17K09046"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Cav3.2 T-type Ca2+ channel activity by H2S, generated by upregulated cystathionine-\u03b3-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1\/RAGE and CSE\/H2S\/Cav3.2 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 Ca2+ channels or CSE, and genetic deletion of Cav3.2. 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 P2X4\/P2X7 receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X7\/P2X4, and caused HMGB1 release via P2X7 in RAW264.7 cells, which was dependent on p38MAPK\/NF-\u03baB 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 H2S-targeted Cav3.2-dependent nociceptor excitation, resulting in bladder pain.<\/jats:p>","DOI":"10.3390\/cells9081748","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T05:10:30Z","timestamp":1595394630000},"page":"1748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H2S\/Cav3.2 Signaling in Mice"],"prefix":"10.3390","volume":"9","author":[{"given":"Shiori","family":"Hiramoto","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Tsubota","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Sakaegi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Toriyama","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"},{"name":"Division of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiko","family":"Sekiguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Known as Kinki University), Higashi-Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Ishikura","sequence":"additional","affiliation":[{"name":"Division of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0160-7379","authenticated-orcid":false,"given":"Hidenori","family":"Wake","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Nishibori","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy Du","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Okada","sequence":"additional","affiliation":[{"name":"Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9568-1528","authenticated-orcid":false,"given":"Naoki","family":"Toyooka","sequence":"additional","affiliation":[{"name":"Faculty of Engineering, University of Toyama, Toyama 930-8555, 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