TrkA inhibition alleviates bladder overactivity in cyclophosphamide-induced cystitis by targeting hyperpolarization-activated cyclic nucleotide-gated channels.
TrkA inhibition alleviates bladder overactivity in cyclophosphamide-induced cystitis by targeting hyperpolarization-activated cyclic nucleotide-gated channels.
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DOI：
10.22038/ijbms.2023.68528.14943
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发表时间：
2023
影响因子：
2.2
通讯作者：
中科院分区：
文献类型：
--
作者：
探讨原肌球蛋白受体激酶A（TrkA）治疗间质性膀胱炎/膀胱疼痛综合征（IC/BPS）的可能性。将64只雌性大鼠随机分配至对照组和环磷酰胺（环磷酰胺）组。采用定量逆转录聚合酶链反应（RT-PCR）检测TrkA mRNA水平。Western blot分析TNF-α、IL-6和TrkA蛋白水平。免疫组化法检测膀胱组织中TrkA的表达。收缩力研究和尿动力学测量分别用于测试逼尿肌条的自发收缩和整体膀胱活动。成功建立大鼠慢性膀胱炎模型。CYP处理组大鼠膀胱中TrkA的mRNA和蛋白水平显著升高。免疫组织化学染色和免疫荧光染色结果显示，膀胱灌注组TrkA表达增加主要见于膀胱黏膜层和膀胱间质Cajal样细胞（ICC-LCs），而逼尿肌平滑肌细胞未见表达。TrkA的特异性抑制剂GW 441756（10 μM）显著抑制了CYP组大鼠逼尿肌肌条的强烈自发收缩，并减轻了CYP治疗大鼠的整体膀胱过度活动。然而，在用超极化激活环核苷酸门控（HCN）通道特异性阻断剂ZD 7288（50 μ M）预处理后，GW 441756（10 μ M）对逼尿肌肌条自发收缩和整体膀胱活动的抑制作用被消除。我们的研究结果表明，增加TrkA表达在慢性膀胱炎促进膀胱过度活动的发展，通过靶向HCN通道。
To investigate the potential of Tropomyosin receptor kinase A (TrkA) for the treatment of interstitial cystitis/ bladder pain syndrome (IC/BPS). Sixty-four female rats were randomly assigned to the control and cyclophosphamide (CYP) groups. Quantitative reverse transcription polymerase chain reaction was utilized to detect the mRNA level of TrkA. Western blot analysis was used to measure the protein levels of TNF-α, IL-6, and TrkA. Immunostaining was used to detect the expression of TrkA in bladder sections. Contractility studies and urodynamic measurements were utilized to test the spontaneous contractions of detrusor muscle strips and the global bladder activity, respectively. Rat models of chronic cystitis were successfully established. The mRNA and protein levels of TrkA were significantly increased in the bladders of CYP-treated rats. Also, results of immunohistochemical staining and immunofluorescence staining showed that increased TrkA expression in the CYP group was mainly observed in the urothelium layer and bladder interstitial Cajal-like cells (ICC-LCs) but not in the detrusor smooth muscle cells. The specific inhibitor of TrkA, GW441756 (10 μM), significantly suppressed the robust spontaneous contractions of detrusor muscle strips in the CYP group and alleviated the overall bladder overactivity of CYP-treated rats. However, the inhibitory effects of GW441756 (10 μM) on the spontaneous contractions of detrusor muscle strips and the overall bladder activity were eliminated after pretreatments with the specific blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, ZD7288 (50 μM). Our results suggested that increased TrkA expression during chronic cystitis promotes the development of bladder overactivity by targeting the HCN channels.
影响因子：
5.6
作者：
Brandolini, Laura;Aramini, Andrea;Bianchini, Gianluca;Ruocco, Anna;Bertini, Riccardo;Novelli, Rubina;Angelico, Patrizia;Valsecchi, Anna Elisa;Russo, Roberto;Castelli, Vanessa;Cimini, Annamaria;Allegretti, Marcello
通讯作者：
Allegretti, Marcello
环磷酰胺诱导的间质 Cajal 样细胞中 HCN1 通道上调导致小鼠膀胱过度活跃
影响因子：
12.8
作者：
Liu Q;Long Z;Dong X;Zhang T;Zhao J;Sun B;Zhu J;Li J;Wang Q;Yang Z;Hu X;Li L
通讯作者：
Li L