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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Adenosine Triphosphate/*metabolism ; Calcium Channels, T-Type/*metabolism ; Cystitis, Interstitial/*metabolism ; HMGB1 Protein/*metabolism ; Macrophages/*metabolism ; Signal Transduction/*genetics ; Sulfites/*metabolism; Acrolein/metabolism ; Animals ; Calcium Channels, T-Type/genetics ; Cyclophosphamide/adverse effects ; Cyclophosphamide/metabolism ; Cystathionine gamma-Lyase/metabolism ; Cystitis, Interstitial/chemically induced ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Knockout ; Receptor for Advanced Glycation End Products/metabolism ; Up-Regulation/genetics

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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Keywords: Adenosine triphosphate (ATP); Cav3.2 T-type Ca2+ channel; cyclophosphamide (CPA); cystathionine-γ-lyase (CSE); high mobility group box 1 (HMGB1); hydrogen sulfide (H2S); interstitial cystitis/bladder pain syndrome (IC/BPS); macrophage; reactive oxygen species (ROS); receptor for advanced glycation end products (RAGE)

0 (Ager protein, mouse)
0 (Cacna1h protein, mouse)
0 (Calcium Channels, T-Type)
0 (HMGB1 Protein)
0 (HMGB1 protein, mouse)
0 (Receptor for Advanced Glycation End Products)
0 (Sulfites)
7864XYD3JJ (Acrolein)
8L70Q75FXE (Adenosine Triphosphate)
8N3DW7272P (Cyclophosphamide)
EC 4.4.1.1 (Cystathionine gamma-Lyase)
OJ9787WBLU (hydrogen sulfite)

Date Created: 20200726 Date Completed: 20210310 Latest Revision: 20210310

20250114

PMC7463894

10.3390/cells9081748

32707767