TrkA inhibition alleviates bladder overactivity in cyclophosphamide-induced cystitis by targeting hyperpolarization-activated cyclic nucleotide-gated channels

作者全名："Liu, Qian; Li, Xiaodong; Zhu, Jingzhen; Sun, Bishao; Li, Shadan"

作者地址："[Liu, Qian] Chongqing Med Univ, Clin Med Postdoctoral Res Stn, Affiliated Hosp 1, Chongqing, Peoples R China; [Liu, Qian; Li, Xiaodong; Li, Shadan] Gen Hosp Western Theater Command, Dept Urol, Chengdu, Peoples R China; [Li, Xiaodong] Southwest Med Univ, Dept Urol, Affiliated Hosp, Luzhou, Peoples R China; [Zhu, Jingzhen; Sun, Bishao] Army Med Univ, Affiliated Hosp 2, Dept Urol, Chongqing, Peoples R China"

通信作者："Li, SD (通讯作者)，Gen Hosp Western Theater Command, Dept Urol, Chengdu, Peoples R China.; Sun, BS (通讯作者)，Army Med Univ, Affiliated Hosp 2, Dept Urol, Chongqing, Peoples R China."

来源：IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000988782100012

JCR分区：Q3

影响因子：2.1

年份：2023

卷号：26

期号：6

开始页：701

结束页：707

文献类型：Article

关键词：Cyclophosphamide; Cystitis; activated-cyclic nucleotide; gated channels; kinase A; Urinary bladder; Hyperpolarization

摘要："Objective(s): To investigate the potential of Tropomyosin receptor kinase A (TrkA) for the treatment of interstitial cystitis/ bladder pain syndrome (IC/BPS).Materials and Methods: Sixty-fourfemale 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-alpha, 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. Results: 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 [iM), 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 [iM) 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 [iM). Conclusion: Our results suggested that increased TrkA expression during chronic cystitis promotes the development of bladder overactivity by targeting the HCN channels."

基金机构："National Natural Science Foundation of China [81900691, 82000665]"

基金资助正文：Acknowledgment This work was supported by the National Natural Science Foundation of China (nos. 81900691 and 82000665) .