Deletion of renal Nedd4-2 abolishes the effect of high K(+) intake on Kir4.1/Kir5.1 and NCC activity in the distal convoluted tubule.
Deletion of renal Nedd4-2 abolishes the effect of high K(+) intake on Kir4.1/Kir5.1 and NCC activity in the distal convoluted tubule.
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删除肾Nedd4-2可消除高K(+)摄入对远曲小管Kir4.1/Kir5.1和NCC活性的影响。
DOI：
10.1152/ajprenal.00072.2021
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Lin Dao-Hong
中科院分区：
文献类型：
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作者：
Xiao Yu;Duan Xin-Peng;Zhang Dan-Dan;Wang Wen-Hui;Lin Dao-Hong
高钾饮食摄入抑制了远曲小管（DCT）基底外侧Kir4.1/Kir5.1活性，并且抑制Kir4.1/Kir5.1是抑制NaCl协同转运蛋白（NCC）的关键。在这里，我们研究了神经前体细胞表达的发育下调4-2（Nedd 4 -2）缺失是否会损害HK对DCT基底外侧Kir4.1/Kir5.1和NCC的影响。单通道记录和全细胞记录显示，在肾小管特异性Nedd 4 -2敲除（Ks-Nedd 4 -2 KO）小鼠中，HK既不降低也不增加DCT基底外侧Kir4.1/Kir5.1活性。相比之下，HK抑制和LK增加对照小鼠的Kir4.1/Kir5.1活性[神经前体细胞表达发育下调的4-like（Nedd 4l）flox/flox]。此外，HK摄入量降低的K+电流逆转电位的负性在DCT（去极化），只有在对照组小鼠，但在Ks-Nedd 4 -2 KO小鼠。肾脏清除实验表明，HK摄入量减少，而LK摄入量增加，氢氯噻嗪诱导的肾脏Na+排泄仅在对照小鼠中，但这种作用在Ks-Nedd 4 -2 KO小鼠中不存在。Western blot分析也表明HK诱导的磷酸化NCC（Thr 53）和总NCC的抑制仅在对照小鼠中观察到，而在Ks-Nedd 4 -2 KO小鼠中未观察到。此外，在HK的Ks-Nedd 4 -2 KO小鼠中，上皮Na+通道的所有三个亚基的表达均高于对照小鼠。因此，尽管NCC高表达，但在HK 7天的Nedd 4 lflox/Kl和Ks-Nedd 4 -2 KO小鼠之间的血浆K+浓度相似。结论Nedd 4 -2在调节HK诱导的DCT中Kir4.1/Kir5.1和NCC的抑制中起作用。新&值得注意的是远曲小管中的Kir4.1/Kir5.1在高K+摄入后肾脏K+排泄的调节中起重要作用。我们发现，在肾小管特异性Nedd 4 - 2基因敲除小鼠中，神经前体细胞在发育过程中表达下调的4-2（Nedd 4 -2）在介导K+饮食对Kir4.1/Kir5.1和NaCl协同转运蛋白的影响中起作用，因为高K+摄入未能抑制肾小管特异性Nedd 4 -2基因敲除小鼠基底外侧Kir4.1/Kir5.1和NaCl协同转运蛋白。
High-dietary K+(HK) intake inhibits basolateral Kir4.1/Kir5.1 activity in the distal convoluted tubule (DCT), and HK-induced inhibition of Kir4.1/Kir5.1 is essential for HK-induced inhibition of NaCl cotransporter (NCC). Here, we examined whether neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) deletion compromises the effect of HK on basolateral Kir4.1/Kir5.1 and NCC in the DCT. Single-channel recording and whole cell recording showed that neither HK decreased nor low-dietary K+(LK) increased basolateral Kir4.1/Kir5.1 activity of the DCT in kidney tubule-specific Nedd4-2 knockout (Ks-Nedd4-2 KO) mice. In contrast, HK inhibited and LK increased Kir4.1/Kir5.1 activity in control mice [neural precursor cell expressed developmentally downregulated 4-like(Nedd4l)flox/flox]. Also, HK intake decreased the negativity of K+current reversal potential in the DCT (depolarization) only in control mice but not in Ks-Nedd4-2 KO mice. Renal clearance experiments showed that HK intake decreased, whereas LK intake increased, hydrochlorothiazide-induced renal Na+excretion only in control mice, but this effect was absent in Ks-Nedd4-2 KO mice. Western blot analysis also demonstrated that HK-induced inhibition of phosphorylated NCC (Thr53) and total NCC was observed only in control mice but not in Ks-Nedd4-2 KO mice. Furthermore, expression of all three subunits of the epithelial Na+channel in Ks-Nedd4-2 KO mice on HK was higher than in control mice. Thus, plasma K+concentrations were similar betweenNedd4lflox/floxand Ks-Nedd4-2 KO mice on HK for 7 days despite high NCC expression. We conclude that Nedd4-2 plays a role in regulating HK-induced inhibition of Kir4.1/Kir5.1 and NCC in the DCT.NEW & NOTEWORTHYBasolateral Kir4.1/Kir5.1 in the distal convoluted tubule plays an important role as a “K+sensor” in the regulation of renal K+excretion after high K+intake. We found that neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) a role in mediating the effect of K+diet on Kir4.1/Kir5.1 and NaCl cotransporter because high K+intake failed to inhibit basolateral Kir4.1/Kir5.1 and NaCl cotransporter in kidney tubule-specific Nedd4-2 knockout mice.