WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia
WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia
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DOI：
10.1073/pnas.0308434100
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发表时间：
2004-02-17
影响因子：
11.1
通讯作者：
Lifton, RP
中科院分区：
文献类型：
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作者：
Kahle, KT;Gimenez, I;Lifton, RP
丝氨酸-苏氨酸激酶WNK 4突变[没有赖氨酸（K）4]导致假性醛固酮减少症11型，这是一种以高血压伴高钾血症为特征的孟德尔疾病。在肾脏中，WNK 4通过可变地抑制噻嗪敏感性NaCl协同转运蛋白和K+通道ROMK来调节NaCl重吸收和K+分泌之间的平衡。我们现在证明了WNK 4 mRNA和蛋白质在肾脏外的表达。在肾外组织中，WNK 4几乎仅存在于极化上皮细胞中，与紧密连接、侧膜和细胞质相关。表达WNK 4的上皮包括汗管、结肠隐窝、胰管、胆管和附睾。WNK 4也在血脑屏障的特化内皮中表达。这些上皮细胞和内皮细胞都在Cl-转运中起重要作用。因为已知WNK 4调节肾Cl-处理，所以我们测试了WNK 4对上皮Cl-通量的介质的活性的影响，所述介质的肾外表达与WNK 4重叠。WNK 4被证明是Na+-K+-2Cl（-）协同转运蛋白（NKCC 1）和Cl-/碱交换蛋白SLC 26 A6（CFEX）活性的有效抑制剂。（NKCC 1介导的Rb-86内流抑制>95%，P < 0.001; CFEX介导的[C-14]甲酸盐摄取抑制>80%，P < 0.001），分别是穿过基底外侧膜和顶膜的Cl-通量的介质。相比之下，WNK 4没有表现出抑制pendrin，一个相关的Cl-/碱交换。这些发现表明WNK 4在不同上皮细胞中调节电解质通量的一般作用。此外，他们揭示了WNK 4调节结构上不相关的离子通道，协同转运蛋白和交换剂的各种各样的活动。
Mutations in the serine-threonine kinase WNK4 [with no lysine (K) 4] cause pseudohypoaldosteronism type 11, a Mendelian disease featuring hypertension with hyperkalemia. In the kidney, WNK4 regulates the balance between NaCI 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+-2CI(-) cotransporter (NKCC1) and the Cl-/base exchanger SLC26A6 (CFEX) (>95% inhibition of NKCC1-mediated Rb-86 influx, P < 0.001; >80% inhibition of CFEX-mediated [C-14] 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.