The Na+,K+,2Cl− Cotransporter, Not Aquaporin 1, Sustains Cerebrospinal Fluid Secretion While Controlling Brain K+ Homeostasis

IF 14.3 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Dennis Bo Jensen, Trine L. Toft-Bertelsen, Dagne Barbuskaite, Jane Stubbe, Sandor Nietzsche, Tenna Capion, Nicolas H. Norager, Markus H. Olsen, Andreas T. Sørensen, Henrik Dimke, Christian A. Hübner, Marianne Juhler, Nanna MacAulay
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Abstract

Disturbances in the brain fluid balance can lead to life-threatening elevation in intracranial pressure (ICP), which represents a vast clinical challenge. Targeted and efficient pharmaceutical therapy of elevated ICP is not currently available, as the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved. To resolve the quantitative contribution of key choroid plexus transport proteins, this study employs mice with genetic knockout and/or viral choroid plexus-specific knockdown of aquaporin 1 (AQP1) and the Na+, K+, 2Cl cotransporter 1 (NKCC1) for in vivo determinations of CSF dynamics, ex vivo choroid plexus for transporter-mediated clearance of a CSF K+ load, and patient CSF for [K+] quantification. CSF secretion and ICP management occur independently of choroid plexus AQP1 expression, whereas both parameters are reduced by 40% upon choroid plexus NKCC1 knockdown. Elevation of [K+]CSF increases the choroid plexus Na+/K+-ATPase activity, and favors inwardly-directed net NKCC1 transport, which, together, promote CSF K+ clearance, while maintaining undisturbed CSF secretion rates. CSF from patients with post-hemorrhagic hydrocephalus does not display elevated [K+]CSF, suggesting that NKCC1 maintains net outward transport direction during post-hemorrhagic hydrocephalus formation. Direct or indirect therapeutic modulation of choroid plexus NKCC1 can thus be a potential promising pharmacological approach against brain pathologies associated with elevated ICP.

Abstract Image

Na+,K+,2Cl-共转运体,而不是水通道蛋白1,在控制脑K+稳态的同时维持脑脊液分泌。
脑液平衡紊乱可导致危及生命的颅内压升高,这是一个巨大的临床挑战。由于控制脑脊液(CSF)分泌的分子机制在很大程度上尚不清楚,目前尚无针对ICP升高的有效药物治疗方法。为了解决关键脉络膜丛转运蛋白的定量贡献,本研究使用基因敲除和/或病毒敲除脉络膜丛特异性水通道蛋白1 (AQP1)和Na+, K+, 2Cl-共转运蛋白1 (NKCC1)的小鼠来测定脑脊液动力学,体外脉络膜丛用于转运蛋白介导的脑脊液K+负荷的清除,以及患者脑脊液用于[K+]定量。脑脊液分泌和ICP管理独立于脉络膜丛AQP1的表达,而脉络膜丛NKCC1敲低后,这两个参数都减少了40%。[K+]CSF升高可增加脉络膜丛Na+/K+- atp酶活性,有利于NKCC1向内净转运,两者共同促进CSF K+清除,同时保持未受干扰的CSF分泌率。出血性脑积水患者的脑脊液未显示[K+]脑脊液升高,提示NKCC1在出血性脑积水形成过程中保持净向外运输方向。因此,脉络膜丛NKCC1的直接或间接治疗调节可能是一种潜在的有前途的治疗颅内压升高相关脑病的药理学方法。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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