Endogenous H2S sensitizes PAR4-induced bladder pain
Endogenous H2S sensitizes PAR4-induced bladder pain
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内源性 H2S 使 PAR4 诱发的膀胱疼痛变得敏感
DOI：
10.1152/ajprenal.00526.2017
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhu Yaofeng
中科院分区：
文献类型：
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作者：
Wang Wenfu;Bo Qiyu;Du Jian;Yu Xin;Zhu Kejia;Cui Jianfeng;Zhao Hongda;Wang Yong;Shi Benkang;Zhu Yaofeng
膀胱痛是间质性膀胱炎/痛性膀胱综合征的显著症状。胱硫醚β-合成酶或胱硫醚γ-裂解酶产生的硫化氢促进了膀胱的超敏反应。我们评估了H_2S通路在蛋白酶激活受体4(PAR4)诱导的膀胱痛中的作用。小鼠膀胱内注入PAR4激活肽建立膀胱痛模型。通过预先给予D、L-丙烯酰甘氨酸、氨基氧乙酸、ORS-腺苷蛋氨酸或膀胱内注射NaHS来评价H_2S在该模型中的作用。用同样的方法处理SV-Huc-1细胞。评估CBS、CSE和巨噬细胞移动抑制因子(MIF)的表达、膀胱排尿功能、膀胱炎症、硫化氢产生和相关的膀胱痛。CSE和CBS通路在小鼠膀胱和SV-Huc-1细胞中均存在。在PAR4诱导的膀胱疼痛模型中，H_2S信号转导上调，在人膀胱、小鼠膀胱和SV-Huc-1细胞中H_2S生成酶活性上调。预先给予AOAA或NaHS分别抑制或促进PAR4诱导的机械性痛敏，而PAG仅部分抑制PAR4诱导的膀胱痛。经PAG或AOAA处理后，小鼠膀胱和SV-Huc-1细胞的硫化氢生成量均减少。AOAA可增加膀胱组织和细胞中MIF蛋白的表达，而NaHS可降低MIF蛋白的表达。由硫化氢途径引发的膀胱疼痛不伴有炎症或排尿行为改变。因此，CBS或CSE产生的内源性H_2S通过MIF在PAR4诱导的膀胱疼痛小鼠中引起牵涉性痛敏，而不会造成膀胱损伤或改变排尿行为。
Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (H2S) generated by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) facilitates bladder hypersensitivity. We assessed involvement of the H2S pathway in protease-activated receptor 4 (PAR4)-induced bladder pain. A bladder pain model was induced by intravesical instillation of PAR4-activating peptide in mice. The role of H2S in this model was evaluated by intraperitoneal preadministration ofd,l-propargylglycine (PAG), aminooxyacetic acid (AOAA), orS-adenosylmethionine or the preintravesical administration of NaHS. SV-HUC-1 cells were treated in similar manners. Assessments of CBS, CSE, and macrophage migration inhibitory factor (MIF) expression, bladder voiding function, bladder inflammation, H2S production, and referred bladder pain were performed. The CSE and CBS pathways existed in both mouse bladders and SV-HUC-1 cells. H2S signaling was upregulated in PAR4-induced bladder pain models, and H2S-generating enzyme activity was upregulated in human bladders, mouse bladders, and SV-HUC-1 cells. Pretreatment with AOAA or NaHS inhibited or promoted PAR4-induced mechanical hyperalgesia, respectively; however, PAG only partially inhibited PAR4-induced bladder pain. Treatment with PAG or AOAA decreased H2S production in both mouse bladders and SV-HUC-1 cells. Pretreatment with AOAA increased MIF protein levels in bladder tissues and cells, whereas pretreatment with NaHS lowered MIF protein levels. Bladder pain triggered by the H2S pathway was not accompanied by inflammation or altered micturition behavior. Thus endogenous H2S generated by CBS or CSE caused referred hyperalgesia mediated through MIF in mice with PAR4-induced bladder pain, without causing bladder injury or altering micturition behavior.