Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule.
Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule.
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Na/K-ATP酶信号强直性抑制肾近曲小管中的钠重吸收。
DOI：
10.1096/fj.202200785rr
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Blan
中科院分区：
文献类型：
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作者：
Mukherji,ShreyaT;Brambilla,Luca;Stuart,KaileyB;Mayes,Isabella;Kutz,LauraC;Chen,Yiliang;Barbosa,LeandroA;Elmadbouh,Ibrahim;McDermott,JeffP;Haller,StevenT;Romero,MichaelF;Soleimani,Manoocher;Liu,Jiang;Shapiro,JosephI;Blan
通过其经典的ATP依赖性离子泵功能，基底外侧Na/K-ATP酶（NKA）产生Na+梯度，驱动肾近端小管（RPT）中的顶端Na+重吸收，主要通过Na+/H+交换器（NHE 3）。因此，NKA介导的离子转运的激活通过激活基底外侧（NKA）和顶端（NHE 3）Na+重吸收减少尿钠排泄。相比之下，最近发现的NKA信号传导功能的激活触发RPT NKA和NHE 3的细胞再分布并减少Na+重吸收。我们使用基因靶向来测试NKA信号传导和离子泵送对RPT Na+重吸收的整体调节的各自贡献。在细胞和小鼠中RPT NKA的敲低增加了膜NHE 3和Na+/HCO 3 −协同转运蛋白（NBCe 1A）。尿量和绝对Na+排泄量减少65%，这是由于RPT Na+重吸收增加（如锂清除率降低和肾小球滤过率不变所示），并伴有血压升高。这种高重吸收表型在与RPT NHE 3 −/−小鼠杂交后得到拯救，证实了NKA/NHE 3偶联的重要性。因此，NKA信号通过调节关键的顶侧和基底侧Na+转运体对Na+重吸收施加紧张性抑制。这种作用在NKA基因抑制后解除，紧张性地抵消了NKA的ATP驱动的基底外侧Na+重吸收功能。引人注目的是，NKA信号不仅是生理相关的，但它也似乎是功能上占主导地位的NKA离子泵在RPT重吸收的控制。
Through its classic ATP‐dependent ion‐pumping function, basolateral Na/K‐ATPase (NKA) generates the Na+gradient that drives apical Na+reabsorption in the renal proximal tubule (RPT), primarily through the Na+/H+exchanger (NHE3). Accordingly, activation of NKA‐mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na+reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na+reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na+reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na+/HCO3−cotransporter (NBCe1A). Urine output and absolute Na+excretion decreased by 65%, driven by increased RPT Na+reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3−/−mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na+reabsorption by regulating key apical and basolateral Na+transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP‐driven function of basolateral Na+reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.