WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia

被引:134
作者
Kahle, KT
Gimenez, I
Hassan, H
Wilson, FH
Wong, RD
Forbush, B
Aronson, PS
Lifton, RP [1 ]
机构
[1] Howard Hughes Med Inst, Dept Genet, New Haven, CT 06510 USA
[2] Howard Hughes Med Inst, Dept Med, New Haven, CT 06510 USA
[3] Howard Hughes Med Inst, Dept Mol Biophys & Biochem, New Haven, CT 06510 USA
[4] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA
[5] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA
关键词
D O I
10.1073/pnas.0308434100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:2064 / 2069
页数:6
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