Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria.
Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria.
复制标题
NCX2 的基因敲除和药物抑制会导致钠尿和高钙尿症。
DOI：
10.1016/j.bbrc.2014.12.016
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Iwamoto T
中科院分区：
文献类型：
--
作者：
Gotoh Y;Kita S;Fujii M;Tagashira H;Horie I;Arai Y;Uchida S;Iwamoto T
Na+/Ca 2+交换器（NCX）是一种受膜电位和Na+和Ca 2+跨膜梯度控制的双向转运蛋白。虽然NCX 1和NCX 2的两种亚型在远端肾单位的基底外侧膜上共表达，但这些亚型的功能意义尚不完全清楚。因此，我们使用NCX 1-和NCX 2-杂合子敲除小鼠（KO）和它们的双KO，以及亚型选择性NCX抑制剂，以确定NCX亚型在小鼠尿液形成和电解质排泄中的作用。NCX抑制剂，特别是NCX 2敏感性抑制剂，引起剂量依赖性尿钠排泄，并且在较高剂量下，还引起高钙尿症。一致地，NCX 1-KO具有与野生型小鼠（WT）相似的正常肾功能，而NCX 2-KO和双KO表现出中度尿钠和高钙尿。值得注意的是，在NCX 1-KO和WT中观察到对YM-244769的肾脏反应相当，但在NCX 2-KO和双KO中消失。因此，NCX 2的功能抑制最初引起尿钠排泄，进一步抑制NCX 2产生高钙尿，表明NCX 2的功能意义在于肾脏的Na+和Ca 2+重吸收。
The Na+/Ca2+exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+and Ca2+. Although two isoforms of NCX1 and NCX2 are coexpressed on the basolateral membrane of the distal nephron, the functional significance of these isoforms is not entirely clear. Therefore, we used NCX1- and NCX2-heterozygote knockout mice (KO) and their double KO, as well as isoform-selective NCX inhibitors, to determine the roles of NCX isoforms in urine formation and electrolyte excretion in mice. NCX inhibitors, particularly NCX2-sensitive inhibitors, caused a dose-dependent natriuresis and in a higher dose, moreover, hypercalciuria. Consistently, NCX1-KO possessed normal renal function similar to wild-type mice (WT), whereas NCX2-KO and double KO exhibited moderate natriuresis and hypercalciuria. Notably, renal responses to YM-244769 were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO. Thus, functional inhibition of NCX2 initially causes natriuresis, and further inhibition of NCX2 produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na+and Ca2+reabsorption of the kidney.