[1]周浩,王珺,姬广聚,等.FKBP12.6敲除对小鼠逼尿肌过度活动的影响及其机制研究[J].第三军医大学学报,2019,41(22):2146-2151.
 ZHOU Hao,WANG Jun,JI Guangju,et al.FK506 binding protein 12.6 knockout exacerbates detrusor overactivity in mice possibly by down-regulating ryanodine receptor 2[J].J Third Mil Med Univ,2019,41(22):2146-2151.
点击复制

FKBP12.6敲除对小鼠逼尿肌过度活动的影响及其机制研究(/HTML )
分享到:

《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第22期
页码:
2146-2151
栏目:
基础医学
出版日期:
2019-11-30

文章信息/Info

Title:
FK506 binding protein 12.6 knockout exacerbates detrusor overactivity in mice possibly by down-regulating ryanodine receptor 2
作者:
周浩王珺姬广聚郑霁周占松
陆军军医大学(第三军医大学)第一附属医院全军泌尿外科研究所1;中国科学院生物物理研究所交叉科学所重点实验室
Author(s):
ZHOU Hao WANG Jun JI Guangju ZHENG Ji ZHOU Zhansong

Institute of Urology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038; 2Key Laboratory of Interdisciplinary Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100020, China

关键词:
他克莫司结合蛋白12.6逼尿肌过度活动雷尼丁受体2小鼠
Keywords:
FK506 binding protein 12.6 urinary bladder overactive ryanodine receptor 2 mice
分类号:
R322.62;R349-33;R694.52
文献标志码:
A
摘要:

目的 探讨他克莫司结合蛋白12.6(FK506 binding protein 12.6, FKBP12.6)敲除对小鼠逼尿肌过度活动(detrusor overactivity, DO)的影响及其作用机制。方法 8~10周龄129系雌性野生型(WT组)和FKBP12.6基因敲除小鼠(纯合子, KO组)各30只,通过膀胱出口部分梗阻(partial bladder outlet obstruction, PBOO)建立小鼠DO模型。HE染色观察2组小鼠膀胱逼尿肌形态,尿斑实验(3 h内小鼠的排尿情况)比较尿频症状,尿动力学实验比较储尿末期膀胱压力变化情况,腹腔脏器充盈反应(visceromotor responses, VMRs)及膀胱平滑肌充盈期电活动比较膀胱对压力的反应情况,膀胱平滑肌肌条自发性收缩实验判断其对张力的敏感性,Western blot比较雷尼丁受体2(Ryanodine Receptor 2, RyR2)表达的变化。结果FKBP12.6敲除不会使小鼠逼尿肌形态发生明显的改变,但能加重小鼠尿频症状:与WT组比较,KO组排尿次数明显增多[(43.500±19.164) vs (22.000±14.717) 次/3 h, P<0.05];使DO模型鼠储尿末期DO程度更加严重:与WT组比较, KO组储尿期膀胱压力的波动次数明显增加[(13.900±5.430) vs (8.000±3.232) 次/30 min, P<0.05];并使小鼠逼尿肌条对张力的敏感性增高(3.200±0.648 vs 1.200±0.245, P<0.01)。与WT组比较,FKBP12.6敲除小鼠RyR2表达出现明显下调(0.154±0.106 vs 1.000±0.444, P<0.01)。结论 FKBP12.6基因敲除可能通过下调RyR2导致小鼠DO程度加重。

Abstract:

Objective To investigate the effect of FK506 binding protein 12.6 (FKBP12.6) knockout on detrusor overactivity (DO) in mice and explore the possible mechanism. MethodsMouse models of DO were established by partial bladder outlet obstruction (PBOO) in 30 wild-type mice (WT) and 30 homozygote FKBP12.6 knockout mice (KO group). All the mice were 8-10 weeks old and female. The morphology of the detrusor was observed using HE staining, and void spots and urodynamic test were used to assess the changes in the symptom of frequent urinary and the bladder pressure, respectively. Visceromotor responses (VMRs) and bladder smooth muscle electrical activity in the filling stage were recorded to assess the bladder response to pressure. Spontaneous contraction of the detrusor strips was tested to evaluate the sensitivity of the detrusor to tension, and the expression of ryanodine receptor 2 (RyR2) was detected using Western blotting. ResultsFKBP12.6 knockout did not cause obvious changes in detrusor morphology, but aggravated the symptom of frequent urination in the mice. Compared with WT mice, the mice in KO group showed a significantly increased micturition frequency (43.500±19.164 vs 22.000±14.717 every 3 h, P<0.05) with aggravated DO, significantly increased fluctuation frequency of bladder pressure during the urine storage period (13.900±5.430 vs 8.000±3.232 per 30 min, P<0.05), and significantly increased sensitivity of the detrusors to tension (3.200±0.648 vs 1.200±0.245, P<0.01). RyR2 expression in the detrusors decreased significantly in FKBP12.6 knockout mice as compared with the WT mice (0.154±0.106 vs 1.000±0.444, P<0.01). ConclusionFKBP12.6 knockout results in aggravation of DO in mouse models possibly by down-regulation of RyR2 in the detrusors.

参考文献/References:

[1]SERATI M, GHEZZI F. Severity of symptoms of overactive bladder:  a predictor of success and of failure[J]. Eur Urol, 2015, 67(1):  15-16. DOI: 10.1016/j.eururo.2014.07.018.
[2]GINSBERG D A, SCHNEIDER L K, WATANABE T K. Improving outcomes in patients with refractory idiopathic and neurogenic detrusor overactivity:  management strategies[J]. Arch Phys Med Rehabil, 2015, 96(9 Suppl):  S341-S357.e1. DOI: 10.1016/j.apmr.2015.05.016.
[3]XIN W K, SODER R P, CHENG Q P, et al. Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle:  role for ryanodine receptor-mediated BK channel activation[J]. Am J Physiol,Cell Physiol, 2012, 303(10):  C1079-C1089. DOI: 10.1152/ajpcell.00162.2012.
[4]PARAJULI S P, ZHENG Y M, LEVIN R, et al. Big-conductance Ca2+-activated K+ channels in physiological and pathophysiological urinary bladder smooth muscle cells[J]. Channels (Austin), 2016, 10(5):  355-364. DOI: 10.1080/19336950.2016.1180488.
[5]JIANG HH, SONG B, LU G S, et al. Loss of ryanodine receptor calcium-release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model[J]. BJU Int, 2005, 96(3):  428-433. DOI: 10.1111/j.1464-410X.2005.05644.x.
[6]WEHRENS X H, LEHNART S E, HUANG F N, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death[J]. Cell, 2003, 113(7):  829-840. DOI: 10.1016/s0092-8674(03)00434-3.
[7]ZHAO Y T, GUO Y B, GU L,et al. Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes[J]. Cardiovasc Res, 2017, 113(3):  332-342. DOI: 10.1093/cvr/cvw247.
[8]KOIDE M, NYSTORIAK M A, KRISHNAMOORTHY G, et al. Reduced Ca2+ spark activity after subarachnoid hemorrhage disables BK channel control of cerebral artery tone[J]. J Cereb Blood Flow Metab, 2011, 31(1):  3-16. DOI: 10.1038/jcbfm.2010.143.
[9]LI Y H, HE M K, LIN W Y, et al. Responses of bladder smooth muscle to the stretch go through extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/nuclear factor-κB (NF-κB) pathway[J]. Neurourol Urodyn, 2019, 38(6):  1504-1516. DOI: 10.1002/nau.24003.
[10]POWERS S A, RYAN T E, PAK E S,et al. Chronic high-fat diet decreased detrusor mitochondrial respiration and increased nerve-mediated contractions[J]. Neurourol Urodyn, 2019, 38(6):  1524-1532. DOI: 10.1002/nau.24015.
[11]SCHWARTZ E S, LA J H, YOUNG EE, et al. Chronic prostatitis induces bladder hypersensitivity and sensitizes bladder afferents in the mouse[J]. J Urol, 2016, 196(3):  892-901. DOI: 10.1016/j.juro.2016.03.077.
[12]YUAN Q, CHEN Z, SANTULLI G,et al. Functional role of Calstabin2 in age-related cardiac alterations[J]. Sci Rep, 2014, 4:  7425. DOI: 10.1038/srep07425.
[13]LI L K, JIANG C H, SONG B, et al. Altered expression of calcium-activated K and Cl channels in detrusor overactivity of rats with partial bladder outlet obstruction[J]. BJU Int, 2008, 101(12):  1588-1594. DOI: 10.1111/j.1464-410X.2008.07522.x.
[14]HOTTA S, MORIMURA K, OHYA S,et al. Ryanodine receptor type 2 deficiency changes excitation-contraction coupling and membrane potential in urinary bladder smooth muscle[J]. J Physiol (Lond), 2007, 582(Pt 2):  489-506. DOI: 10.1113/jphysiol.2007.130302.
[15]PETKOV G V. Central role of the BK channel in urinary bladder smooth muscle physiology andpathophysiology[J]. Am J Physiol Regul Integr Comp Physiol, 2014, 307(6):  R571-R584. DOI: 10.1152/ajpregu.00142.2014.
[16]WEHRENS X H, LEHNART S E,REIKEN S R, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2[J]. Science, 2004, 304(5668):  292-296. DOI: 10.1126/science.1094301.
[17]TANG W X, CHEN Y F, ZOU A P,et al. Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle[J]. Am J Physiol Heart Circ Physiol, 2002, 282(4):  H1304-H1310. DOI: 10.1152/ajpheart.00843.2001.
[18]LIAO B, ZHENG Y M, YADAV V R,et al. Hypoxia induces intracellular Ca2+ release by causing reactive oxygen species-mediated dissociation of FK506-binding protein 12.6 from ryanodine receptor 2 in pulmonary artery myocytes[J]. Antioxid Redox Signal, 2011, 14(1):  37-47. DOI: 10.1089/ars.2009.3047.
[19]DU Y, ZHAO J H, LI X, et al. Dissociation of FK506-binding protein 12.6 kD from ryanodine receptor in bronchial smooth muscle cells in airway hyperresponsiveness in asthma[J]. Am J Respir Cell Mol Biol, 2014, 50(2):  398-408. DOI: 10.1165/rcmb.2013-0222OC.
[20]NOGUCHI N, YOSHIKAWA T, IKEDA T,et al. FKBP12.6 disruption impairs glucose-induced insulin secretion[J]. Biochem Biophys Res Commun, 2008, 371(4):  735-740. DOI: 10.1016/j.bbrc.2008.04.142.
 

相似文献/References:

[1]卢根生,宋波.逼尿肌过度活动的研究进展[J].第三军医大学学报,2006,28(10):1128.
[2]王军,宋波,金锡御,等.激光共聚焦显微镜观察三磷酸肌醇对大鼠逼尿肌细胞内钙的影响[J].第三军医大学学报,2007,29(01):78.
 WANG Jun,SONG Bo,JIN Xi-yu,et al.Effect of inositol (1,4,5)-trisphosphate on intracellular calcium in rat detrusor cells[J].J Third Mil Med Univ,2007,29(22):78.

更新日期/Last Update: 2019-11-21