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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >WNK4 regulates apical and basolateral Cl~- flux in extrarenal epithelia
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WNK4 regulates apical and basolateral Cl~- flux in extrarenal epithelia

机译：WNK4调节肾上皮上皮的顶端和基底外侧Cl〜-通量

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Mutations in the serine-threonine kinase WNK4 [with no lysine (K) 4] cause pseudohypoaldosteronism type II, a Mendelian disease featuring hypertension with hyperkalemia. In the kidney, WNK4 regulates the balance between NaCl reabsorption and K~+ secretion via variable inhibition of the thiazide-sensistive NaCl cotransporter and the K~+ channel ROMK. We now demonstrate expression of WNK4 mRNA and protein outside the kidney. In extrarenal tissues, WNK4 is found almost exclusively in polarized epithelia, variably associating with tight junctions, lateral membranes, and cytoplasm. Epithelia expressing WNK4 include sweat ducts, colonic crypts, pancreatic ducts, bile ducts, and epididymis. WNK4 is also expressed in the specialized endothelium of the blood-brain barrier. These epithelia and endothelium all play important roles in Cl~- transport. Because WNK4 is known to regulate renal Cl handling, we tested WNK4's effect on the activity of mediators of epithelial Cl~- flux whose extrarenal expression overlaps with WNK4. WNK4 proved to be a potent inhibitor of the activity of both the Na~+-K~+-2Cl~- cotransporter (NKCC1) and the Cl~-/base exchanger SLC26A6 (CFEX) (>95% inhibition of NKCC1-mediated ~(86)Rb influx, P < 0.001; >80% inhibition of CFEX-mediated [~(14)C] formate uptake, P < 0.001), mediators of Cl~- flux across basolateral and apical membranes, respectively. In contrast, WNK4 showed no inhibition of pendrin, a related Cl~-/base exchanger. These findings indicate a general role for WNK4 in the regulation of electrolyte flux in diverse epithelia. Moreover, they reveal that WNK4 regulates the activities of a diverse group of structurally unrelated ion channels, cotransporters, and exchangers.
机译：丝氨酸-苏氨酸激酶WNK4的突变[不含赖氨酸（K）4]导致II型假性低醛固酮增多症，这是一种孟德尔疾病，以高钾血症为高血压。在肾脏中，WNK4通过抑制噻嗪类NaCl协同转运蛋白和K〜+通道ROMK调节NaCl重吸收和K〜+分泌之间的平衡。现在，我们证明肾脏外WNK4 mRNA和蛋白的表达。在肾外组织中，WNK4几乎仅在极化的上皮细胞中发现，并与紧密连接，外侧膜和细胞质发生变化。表达WNK4的上皮细胞包括汗管，结肠隐窝，胰管，胆管和附睾。 WNK4也表达在血脑屏障的专门内皮中。这些上皮和内皮都在Cl-转运中起重要作用。因为已知WNK4调节肾Cl的处理，所以我们测试了WNK4对肾外表达与WNK4重叠的上皮Cl〜-通量介体活性的影响。 WNK4被证明是Na〜+ -K〜+ -2Cl〜-共转运蛋白（NKCC1）和Cl〜-/碱基交换子SLC26A6（CFEX）活性的有效抑制剂（> 95％的NKCC1介导的〜 （86）Rb涌入，P <0.001；对CFEX介导的[〜（14）C]甲酸摄取的抑制作用> 80％，P <0.001），分别是跨基底外侧和顶膜的Cl〜-通量的介质。相反，WNK4没有显示出对Pendrin（一种相关的Cl- /碱基交换剂）的抑制作用。这些发现表明WNK4在多种上皮细胞的电解质通量调节中的一般作用。此外，他们揭示了WNK4调节了结构上不相关的离子通道，共转运蛋白和交换剂的多样性。

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