WNK4 enhances TRPV5-mediated calcium transport:: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4
WNK4 enhances TRPV5-mediated calcium transport:: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4
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DOI：
10.1152/ajprenal.00187.2006
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发表时间：
2007-02-01
影响因子：
4.2
通讯作者：
Peng, Ji-Bin
中科院分区：
文献类型：
--
作者：
Jiang, Yi;Ferguson, William B.;Peng, Ji-Bin
上皮钙通道TRPV 5是肾脏远曲小管和连接小管活性钙重吸收的守门人。WNK 4是一种蛋白丝氨酸/苏氨酸激酶，具有引起家族性高钾血症高血压（FHH）（包括高钙尿症亚型）的基因突变，也位于肾单位的远端小管中。为了了解WNK 4在调节Ca 2+重吸收中的作用，我们评估了WNK 4对非洲爪蟾卵母细胞中TRPV 5介导的Ca 2+转运的影响。TRPV 5与WNK 4的共表达导致TRPV 5介导的Ca 2+摄取增加两倍。Ca 2+摄取的增加是由于TRPV 5表面表达的增加。当共表达噻嗪敏感性Na+-Cl-共转运蛋白NCC时，NCC以剂量依赖性方式减弱WNK 4对TRPV 5的作用。尽管WNK 4致病突变体E562 K、D564 A、Q565 E和R1185 C保留了上调TRPV 5的能力，但当野生型WNK 4被Q565 E突变体取代时，NCC的阻断作用进一步加强，Q565 E突变体导致FHH伴高钙尿。我们的结论是，WNK 4正调控TRPV 5介导的Ca 2+转运和NCC对这一过程的抑制作用可能参与了由WNK 4基因突变引起的FHH高钙尿症的发病机制。
The epithelial Ca2+ channel TRPV5 serves as a gatekeeper for active Ca2+ reabsorption in the distal convoluted tubule and connecting tubule of the kidney. WNK4, a protein serine/threonine kinase with gene mutations that cause familial hyperkalemic hypertension (FHH), including a subtype with hypercalciuria, is also localized in the distal tubule of the nephron. To understand the role of WNK4 in modulation of Ca2+ reabsorption, we evaluated the effect of WNK4 on TRPV5-mediated Ca2+ transport in Xenopus laevis oocytes. Coexpression of TRPV5 with WNK4 resulted in a twofold increase in TRPV5-mediated Ca2+ uptake. The increase in Ca2+ uptake was due to the increase in surface expression of TRPV5. When the thiazide-sensitive Na+-Cl- cotransporter NCC was coexpressed, the effect of WNK4 on TRPV5 was weakened by NCC in a dose-dependent manner. Although the WNK4 disease-causing mutants E562K, D564A, Q565E, and R1185C retained their ability to upregulate TRPV5, the blocking effect of NCC was further strengthened when wild-type WNK4 was replaced by the Q565E mutant, which causes FHH with hypercalciuria. We conclude that WNK4 positively regulates TRPV5-mediated Ca2+ transport and that the inhibitory effect of NCC on this process may be involved in the pathogenesis of hypercalciuria of FHH caused by gene mutation in WNK4.