Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na+-HCO3- Cotransporter Electrogenic 2 Deficiency.
Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na+-HCO3- Cotransporter Electrogenic 2 Deficiency.
复制标题
DOI：
10.1161/hypertensionaha.115.05394
复制
发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Sansom SC
中科院分区：
文献类型：
--
作者：
Wen D;Yuan Y;Warner PC;Wang B;Cornelius RJ;Wang-France J;Li H;Boettger T;Sansom SC
基因SLC 4A 5编码Na+-HCO 3 −共转运蛋白产电2（NBCe 2），位于远端肾单位。遗传删除NBCe 2（KO）导致Na+潴留和高血压，这是一种随着碱负荷减少的表型。我们用酸负荷小鼠进行了实验，并确定是否过度活跃的上皮Na+通道（ENaC）或Na+-Cl−协同转运蛋白（NCC）导致KO中的Na+潴留和高血压。在未治疗的小鼠中，KO的平均动脉压（MAP）高于野生型（WT）;然而，用阿米洛利（ENaC阻断剂）治疗消除了这种差异。相反，氢氯噻嗪（HCTZ），NCC的抑制剂，降低WT的MAP，但不KO。Western blot结果显示，KO组质膜全长ENaC-α表达量显著高于WT组。阿米洛利治疗引起2倍更大的增加Na+排泄KO，WT相比。在KO中，而不是WT，阿米洛利治疗降低血浆[Na+]和尿K+排泄，但增加红细胞压积和血浆[K+]显着。微电极微穿刺结果显示KO组晚期远端小管（LDT）的[K+]明显高于WT组，跨上皮电位（Vte）明显低于WT组。KO中的Vte降低是阿米洛利敏感的，因此揭示了在该节段中产电ENaC介导的Na+重吸收的上调。这些结果表明，在LDT中不存在NBCe 2的情况下，酸负荷小鼠表现出ENaC介导的Na+重吸收的去抑制，这导致Na+潴留、K+消耗和高血压。
The gene SLC4A5 encodes the Na+-HCO3− co-transporter electrogenic 2 (NBCe2), which is located in the distal nephron. Genetically deleting NBCe2 (KO) causes Na+-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether over-active epithelial Na+ channels (ENaC) or the Na+-Cl− co-transporter (NCC) causes the Na+ retention and hypertension in KO. In untreated mice, the mean arterial pressure (MAP) was higher in KO, compared with wild type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide (HCTZ), an inhibitor of NCC, decreased MAP in WT, but not KO. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significant higher in KO than in WT. Amiloride treatment caused a 2-fold greater increase in Na+ excretion in KO, compared with WT. In KO, but not WT, amiloride treatment decreased plasma [Na+] and urinary K+ excretion, but increased hematocrit and plasma [K+] significantly. Micropuncture with microelectrodes showed that the [K+] was significantly higher and the transepithelial potential (Vte) was significantly lower in the late distal tubule (LDT) of the KO compared with WT. The reduced Vte in KO was amiloride-sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na+ reabsorption in this segment. These results show that, in the absence of NBCe2 in the LDT, acid-loaded mice exhibit disinhibition of ENaC-mediated Na+ reabsorption, which results in Na+ retention, K+ wasting, and hypertension.