KCC2氯离子转运体活化对脊髓损伤小鼠逼尿肌过度活动的治疗作用。

IF 3.7 2区 医学 Q1 PHYSIOLOGY
Kyohei Watanabe, Masaru Ishibashi, Takahisa Suzuki, Atsushi Otsuka, Naoki Yoshimura, Hideaki Miyake, Atsuo Fukuda
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引用次数: 0

摘要

本研究旨在阐明腰骶脊髓骶副交感神经核(SPN)中K+- cl -共转运蛋白2 (KCC2)的下调是否会导致脊髓损伤(SCI)中细胞亢进并引发逼尿肌过度活动(DO)。雌性C57BL/6小鼠脊髓Th8-9横断产生脊髓损伤。在脊髓损伤后4周,给予KCC2激活剂CLP290,并进行膀胱测量。然后用免疫组织化学检测SPN神经节前胆碱能副交感神经细胞c-fos染色的神经元活性和KCC2的表达。通过脊髓切片的细胞外记录来评价SPN区神经元的放电特性。CLP290治疗显著降低脊髓损伤小鼠的非排尿性收缩。clp290处理组SPN区c-fos阳性细胞数量和胆碱乙酰转移酶阳性细胞中c-fos的共表达量均低于SCI载药处理组。SPN神经元细胞膜上存在KCC2免疫反应性,胆碱乙酰转移酶阳性SPN神经元中KCC2的归一化荧光强度在SCI载具处理组与脊髓完整载具处理组相比降低,但在SCI clp290处理组中恢复。细胞外记录显示,CLP290抑制了脊髓损伤小鼠SPN神经元的高频放电活动。上述结果表明,SCI诱导的DO与KCC2在神经节前副交感神经元中的下调有关,KCC2转运体的激活可以减少DO,增加神经节前副交感神经元中KCC2的表达,减少SPN神经元的放电。这项研究首次提出,激活Cl-转运蛋白K+-Cl-共转运蛋白2可能是通过靶向膀胱传出通路治疗脊髓损伤诱导的逼尿肌过度活动的一种治疗方式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Therapeutic effects of KCC2 chloride transporter activation on detrusor overactivity in mice with spinal cord injury.

This study aimed to clarify whether downregulation of K+-Cl- cotransporter 2 (KCC2) in the sacral parasympathetic nucleus (SPN) of the lumbosacral spinal cord, from which the efferent pathway innervating the bladder originates, causes cellular hyperexcitability and triggers detrusor overactivity (DO) in spinal cord injury (SCI). SCI was produced by Th8-9 spinal cord transection in female C57BL/6 mice. At 4 wk after SCI, CLP290, a KCC2 activator, was administered, and cystometry was performed. Thereafter, neuronal activity with c-fos staining and KCC2 expression in cholinergic preganglionic parasympathetic neurons in the SPN was examined using immunohistochemistry. Firing properties of neurons in the SPN region were evaluated by extracellular recordings in the spinal cord slice preparations. DO evident as nonvoiding contractions was significantly reduced by CLP290 treatment in SCI mice. The number of c-fos-positive cells and coexpression of c-fos in choline acetyltransferase-positive cells were decreased in the SPN region of the SCI CLP290-treated group versus the SCI vehicle-treated group. KCC2 immunoreactivity was present on the cell membrane of SPN neurons and normalized fluorescence intensity of KCC2 in choline acetyltransferase-positive SPN neurons was decreased in the SCI vehicle-treated group versus the spinal intact vehicle-treated group but recovered in the SCI CLP290-treated group. Extracellular recordings showed that CLP290 suppressed the high-frequency firing activity of SPN neurons in SCI mice. These results indicated that SCI-induced DO is associated with downregulation of KCC2 in preganglionic parasympathetic neurons and that activation of KCC2 transporters can reduce DO, increase KCC2 expression in preganglionic parasympathetic neurons, and decrease neuronal firing of SPN neurons in SCI mice.NEW & NOTEWORTHY This study is the first report to suggest that activation of the Cl- transporter K+-Cl- cotransporter 2 may be a therapeutic modality for the treatment of spinal cord injury-induced detrusor overactivity by targeting bladder efferent pathways.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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