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1 Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
* To whom correspondence should be addressed. E-mail: jpeng{at}uab.edu.
The epithelial calcium channel TRPV5 serves as a gatekeeper for active calcium reabsorption in the distal convoluted tubule and connecting tubule of the kidney. WNK4, a protein serine/threonine kinase whose gene mutations 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 modulating calcium reabsorption, we evaluated the effect of WNK4 on TRPV5-mediated calcium transport in Xenopus laevis oocytes. A two-fold increase in TRPV5-mediated calcium uptake was observed by co-expressing TRPV5 with WNK4. The increase in calcium uptake was due to the increase in surface expression of TRPV5. When the thiazide-sensitive sodium-chloride cotransporter NCC was co-expressed, the effect of WNK4 on TRPV5 was weakened by NCC in a dose-dependent manner. While WNK4 disease-causing mutants E562K, D564A, Q565E and R1185C retained their abilities to up-regulate TRPV5, the blocking effect of NCC was further strengthened when wild-type WNK4 was replaced by Q565E mutant, which causes FHH with hypercalciuria. We conclude that WNK4 positively regulates TRPV5-mediated calcium transport and the inhibitory effect of NCC on this process may be involved in the pathogenesis of hypercalciuria of FHH caused by gene mutation in WNK4.
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