Doxorubicin induces detrusor smooth muscle impairments through myosin dysregulation, leading to a risk of lower urinary tract dysfunction
Doxorubicin induces detrusor smooth muscle impairments through myosin dysregulation, leading to a risk of lower urinary tract dysfunction
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DOI：
10.1152/ajprenal.00090.2019
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发表时间：
2019-07-01
影响因子：
4.2
通讯作者：
Cost, Nicholas G.
中科院分区：
文献类型：
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作者：
Iguchi, Nao;Donmez, M. Irfan;Cost, Nicholas G.
细胞毒性化疗是治疗各种儿童恶性肿瘤的基础；然而，已知这些疗法有各种有害的副作用。多柔比星（DOX）是儿童常用的一种化疗药物，众所周知会引起心脏毒性和心肌病。最近的研究表明，DOX损害骨骼和平滑肌功能，并导致患者疲劳和肠道运动异常。在这项研究中，我们验证了系统性给药DOX也会影响膀胱逼尿肌平滑肌（DSM）功能的假设，特别是在年轻时给药时。在BALB/cJ小鼠中，每周接受6次静脉注射DOX (3 mg.kg(-1))，评估其对DSM和膀胱功能的影响。Wk(-1))或生理盐水作为对照组。全身DOX给药导致DSM肥大，排尿频率增加，DSM收缩力明显减弱，随后与对照组相比松弛较慢。基因表达分析显示，与dox诱导的心脏毒性不同，dox给药动物的膀胱没有显示氧化应激标志物的变化；相反，大电导Ca2+激活的K+通道的下调和肌球蛋白轻链激酶表达的改变与肌球蛋白轻链磷酸化的减少相一致。这些结果表明，体内DOX暴露通过参与逼尿肌收缩-松弛机制的分子失调导致DSM功能障碍。总的来说，我们的研究结果表明，接受IX)X治疗的儿童癌症幸存者可能有膀胱功能障碍的风险增加，并从膀胱功能的随访监测中受益。
Cytotoxic chemotherapy is the foundation for the treatment of the wide variety of childhood malignancies; however, these therapies are known to have a variety of deleterious side effects. One common chemotherapy used in children, doxorubicin (DOX), is well known to cause cardiotoxicity and cardiomyopathy. Recent studies have revealed that DOX impairs skeletal and smooth muscle function and contributes to fatigue and abnormal intestinal motility in patients. In this study, we tested the hypothesis that systemic DOX administration also affects detrusor smooth muscle (DSM) function in the urinary bladder, especially when administered at a young age. The effects on the DSM and bladder function were assessed in BALB/cJ mice that received six weekly intravenous injections of DOX (3 mg.kg(-1).wk(-1)) or saline for the control group. Systemic DOX administration resulted in DSM hypertrophy, increased voiding frequency, and a significant attenuation of DSM contractility, followed by a slower relaxation compared with the control group. Gene expression analyses revealed that unlike DOX-induced cardiotoxicity, the bladders from DOX-administered animals showed no changes in oxidative stress markers; instead, downregulation of large-conductance Ca2+-activated K+ channels and altered expression of myosin light-chain kinase coincided with reduced myosin light-chain phosphorylation. These results indicate that in vivo DOX exposure caused DSM dysfunction by dysregulation of molecules involved in the detrusor contractile-relaxation mechanisms. Collectively, our findings suggest that survivors of childhood cancer treated with IX)X may be at increased risk of bladder dysfunction and benefit from followup surveillance of bladder function.