饮食缺钾会刺激钠的重吸收,导致血压升高的风险增加。远曲小管是将血浆K水平与Na-Cl协同转运蛋白(NCC)活性联系起来的主要变阻器。这是通过Kir4.1/5.1的基底外侧膜电位感应发生的;细胞内Cl-减少;WNK4的激活,Ste20/SPS1相关的脯氨酸/富含丙氨酸激酶(SPAK)的相互作用和磷酸化;钙结合蛋白39(cab39)衔接蛋白与SPAK的结合,导致其运输到顶端膜;和SPAK结合,磷酸化,并激活NCC。由于肾脏特异性无赖氨酸(K)激酶1(WNK1)同工型(KS-WNK1)是该途径的另一个参与者,我们研究了其在NCC调控中的功能。我们在DCT中特别消除了KS-WNK1,并证明了WNK4和L-WNK1的表达增加以及NCC的磷酸化增加。与其他KS-WNK1型号一样,小鼠不是高钾血症。虽然野生型小鼠在低饮食K+条件下表现出增加的NCC磷酸化,转运蛋白的磷酸化水平,在KS-WNK1中已经很高,在低K+饮食下没有变化。因此,在没有KS-WNK1的情况下,转运蛋白对低血浆K失去了敏感性。我们还表明,在低K+条件下,在没有KS-WNK1的情况下,没有形成WNK体。在相邻的段中观察到这些物体,不受KS-WNK1靶向的影响。由于我们的数据与全球KS-WNK1淘汰赛的数据总体一致,它们表明DCT是影响KS-WNK1调节的盐运输的主要部分。
Dietary potassium deficiency causes stimulation of sodium reabsorption leading to an increased risk in blood pressure elevation. The distal convoluted tubule (DCT) is the main rheostat linking plasma K+ levels to the activity of the Na-Cl cotransporter (NCC). This occurs through basolateral membrane potential sensing by inwardly rectifying K+ channels (Kir4.1/5.1); decrease in intracellular Cl-; activation of WNK4 and interaction and phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK); binding of calcium-binding protein 39 (cab39) adaptor protein to SPAK, leading to its trafficking to the apical membrane; and SPAK binding, phosphorylation, and activation of NCC. As kidney-specific with-no-lysine kinase 1 (WNK1) isoform (KS-WNK1) is another participant in this pathway, we examined its function in NCC regulation. We eliminated KS-WNK1 specifically in the DCT and demonstrated increased expression of WNK4 and long WNK1 (L-WNK1) and increased phosphorylation of NCC. As in other KS-WNK1 models, the mice were not hyperkalemic. Although wild-type mice under low-dietary K+ conditions demonstrated increased NCC phosphorylation, the phosphorylation levels of the transporter, already high in KS-WNK1, did not change under the low-K+ diet. Thus, in the absence of KS-WNK1, the transporter lost its sensitivity to low plasma K+. We also show that under low K+ conditions, in the absence of KS-WNK1, there was no formation of WNK bodies. These bodies were observed in adjacent segments, not affected by the targeting of KS-WNK1. As our data are overall consistent with those of the global KS-WNK1 knockout, they indicate that the DCT is the predominant segment affecting the salt transport regulated by KS-WNK1.NEW & NOTEWORTHY In this paper, we show that KS-WNK1 is a critical component of the distal convoluted tubule (DCT) K+ switch pathway. Its deletion results in an inability of the DCT to sense changes in plasma potassium. Absence of KS-WNK1 leads to abnormally high levels of WNK4 and L-WNK1 in the DCT, resulting in increased Na-Cl phosphorylation and function. Our data are consistent with KS-WNK1 targeting WNK4 and L-WNK1 to degradation.