Deletion of Kir5.1 abolishes the effect of high Na+ intake on Kir4.1 and Na+-Cl- cotransporter
Deletion of Kir5.1 abolishes the effect of high Na+ intake on Kir4.1 and Na+-Cl- cotransporter
复制标题
Kir5.1 的缺失消除了高 Na( ) 摄入对 Kir4.1 和 Na( )-Cl(-) 协同转运蛋白的影响。
DOI：
10.1152/ajprenal.00004.2021
复制
发表时间：
2021-06-01
影响因子：
4.2
通讯作者：
Lin, Dao-Hong
中科院分区：
文献类型：
--
作者：
Duan, Xin-Peng;Wu, Peng;Lin, Dao-Hong
高钠（HS）摄入通过抑制远曲小管（DCT）基底外侧Kir4.1/Kir5.1抑制醛固酮敏感性远端肾单位上皮Na+通道（ENaC）和Na+ -Cl-协同转运蛋白（NCC），从而增加肾脏Na+排泄，但不影响K+排泄。本研究的目的是探讨Kir5.1的缺失是否会影响HS对NCC表达/活性和肾脏K+排泄的抑制作用。膜片钳实验证明HS不能抑制Kir5.1基因敲除（KO）小鼠DCT基底外侧K+通道，也不能降低DCT的K+电流逆转电位。此外，Kir5.1的缺失不仅增加了Kir4.1，磷酸化NCC和总NCC的表达，而且消除了HS对Kir4.1，磷酸化NCC和总NCC表达的抑制作用和噻嗪诱导的钠尿。此外，在Kir5.1 KO小鼠中，DCT中NCC表达/活性和基底外侧K+通道的低钠诱导刺激不存在。Kir5.1基因敲除后，DCT晚期ENaC电流降低，HS进一步抑制Kir5.1基因敲除小鼠ENaC活性。最后，用改良的肾清除率法测量基础肾K+排泄率表明，长期HS抑制肾K+排泄率，并稳定地增加Kir5.1 KO小鼠的血浆K+水平，但在野生型小鼠中没有。我们得出结论，Kir5.1在介导HS摄入对DCT和NCC活性/表达的基底外侧K+通道的影响中起重要作用。Kir5.1参与维持高钠摄入时肾脏K+排泄能力，在高钠摄入对远曲小管基底外侧K+通道和Na+ -Cl-协同转运蛋白活性/表达的影响中起重要作用。
High sodium (HS) intake inhibited epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron and Na+ -Cl- cotransporter (NCC) by suppressing basolateral Kir4.1/Kir5.1 in the distal convoluted tubule (DCT), thereby increasing renal Na+ excretion but not affecting K+ excretion. The aim of the present study was to explore whether deletion of Kir5.1 compromises the inhibitory effect of HS on NCC expression/activity and renal K+ excretion. Patch-clamp experiments demonstrated that HS failed to inhibit DCT basolateral K+ channels and did not depolarize K+ current reversal potential of the DCT in Kir5.1 knockout (KO) mice. Moreover, deletion of Kir5.1 not only increased the expression of Kir4.1, phospho-NCC, and total NCC but also abolished the inhibitory effect of HS on the expression of Kir4.1, phospho-NCC, and total NCC and thiazide-induced natriuresis. Also, low sodium-induced stimulation of NCC expression/activity and basolateral K+ channels in the DCT were absent in Kir5.1 KO mice. Deletion of Kir5.1 decreased ENaC currents in the late DCT, and HS further inhibited ENaC activity in Kir5.1 KO mice. Finally, measurement of the basal renal K+ excretion rate with the modified renal clearance method demonstrated that longterm HS inhibited the renal K+ excretion rate and steadily increased plasma K+ levels in Kir5.1 KO mice but not in wild-type mice. We conclude that Kir5.1 plays an important role in mediating the effect of HS intake on basolateral K+ channels in the DCT and NCC activity/expression. Kir5.1 is involved in maintaining renal ability of K+ excretion during HS intake.NEW & NOTEWORTHY Kir5.1 plays an important role in mediating the effect of high sodium intake on basolateral K+ channels in the distal convoluted tubule and Na+ -Cl- cotransporter activity/expression.