Department of Physiology, Qiqihar Medical College, Heilongjiang, China.
Department of Pharmacology, New York Medical College, Valhalla, New York.
Am J Physiol Renal Physiol. 2021 Jul 1;321(1):F1-F11. doi: 10.1152/ajprenal.00072.2021. Epub 2021 May 24.
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 ]. 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 (Thr) 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 between and 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. Basolateral 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.
高膳食钾（HK）摄入抑制远曲小管（DCT）基底外侧 Kir4.1/Kir5.1 活性，HK 诱导的 Kir4.1/Kir5.1 抑制对于 HK 诱导的氯化钠共转运蛋白（NCC）抑制至关重要。在这里，我们研究了神经前体细胞表达的发育下调 4-2（Nedd4-2）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表明，HK 既没有降低，也没有低膳食钾（LK）增加肾脏管状特异性 Nedd4-2 敲除（Ks-Nedd4-2 KO）小鼠 DCT 基底外侧 Kir4.1/Kir5.1 活性。相反，HK 抑制和 LK 增加了对照小鼠[神经前体细胞表达的发育下调 4 样]中的 Kir4.1/Kir5.1 活性。此外，HK 摄入仅在对照小鼠中降低，而在 Ks-Nedd4-2 KO 小鼠中增加 DCT 中的 K 电流反转电位的负值（去极化）。肾清除实验表明，HK 摄入降低，而 LK 摄入增加，氢氯噻嗪诱导的肾钠排泄仅在对照小鼠中，而在 Ks-Nedd4-2 KO 小鼠中则没有。Western blot 分析还表明，只有在对照小鼠中观察到 HK 诱导的磷酸化 NCC（Thr）和总 NCC 的抑制，而在 Ks-Nedd4-2 KO 小鼠中则没有。此外，在 HK 上，Ks-Nedd4-2 KO 小鼠的上皮钠通道的所有三个亚基的表达均高于对照小鼠。因此，尽管 NCC 表达较高，但在 HK 上 7 天，与对照小鼠相比，Ks-Nedd4-2 KO 小鼠的血浆 K 浓度相似。我们得出结论，Nedd4-2 在调节 DCT 中 HK 诱导的 Kir4.1/Kir5.1 和 NCC 抑制中起作用。远曲小管中的基底外侧 Kir4.1/Kir5.1 作为“K 传感器”，在高钾摄入后调节肾脏钾排泄中起重要作用。我们发现，神经前体细胞表达的发育下调 4-2（Nedd4-2）在介导钾饮食对 Kir4.1/Kir5.1 和 NaCl 共转运蛋白的影响中起作用，因为高钾摄入未能抑制肾脏管状特异性 Nedd4-2 敲除小鼠中的基底外侧 Kir4.1/Kir5.1 和 NaCl 共转运蛋白。
