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WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4

Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 27 May 2006 ; accepted in final form 30 September 2006

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.

epithelial calcium channel; CaT1; calcium reabsorption; WNK1; TRPV6

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