Konopacka Agnieszka, Qiu Jing, Yao Song T, Greenwood Michael P, Greenwood Mingkwan, Lancaster Thomas, Inoue Wataru, Mecawi Andre de Souza, Vechiato Fernanda M V, de Lima Juliana B M, Coletti Ricardo, Hoe See Ziau, Martin Andrew, Lee Justina, Joseph Marina, Hindmarch Charles, Paton Julian, Antunes-Rodrigues Jose, Bains Jaideep, Murphy David
School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1.
J Neurosci. 2015 Apr 1;35(13):5144-55. doi: 10.1523/JNEUROSCI.4121-14.2015.
The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.
钠-钾-2氯协同转运蛋白2（NKCC2）曾被认为是肾脏特有的。在此我们展示了其在下丘脑-神经垂体系统（HNS）中的表达，在该系统中，渗透压应激后其表达会上调。HNS通过合成和释放神经肽激素精氨酸加压素（AVP）来控制渗透压稳定性。AVP通过血液循环到达肾脏，在那里它促进水分的保留。敲低HNS中的NKCC2对摄入高盐溶液后的液体平衡产生了深远影响——大鼠产生的尿液显著增多，同时液体摄入量和血浆渗透压也增加。由于NKCC2是髓袢利尿剂布美他尼和呋塞米的分子靶点，我们研究了在水平衡紊乱后它们对HNS功能的影响。在体内和下丘脑外植体中，布美他尼都能逆转脱水引起的GABA介导的AVP神经元兴奋，呋塞米则能阻断AVP的释放。因此，在大鼠中，髓袢利尿剂会破坏调节渗透压稳定性的依赖于NKCC2的脑机制。
