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WNK kinases regulate thiazide-sensitive Na-Cl cotransport
Chao-Ling Yang, … , Rose Mitchell, David H. Ellison
Chao-Ling Yang, … , Rose Mitchell, David H. Ellison
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):1039-1045. https://doi.org/10.1172/JCI17443.
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Article Cardiology

WNK kinases regulate thiazide-sensitive Na-Cl cotransport

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Abstract

Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.

Authors

Chao-Ling Yang, Jordan Angell, Rose Mitchell, David H. Ellison

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Figure 1

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(a) Effect of WNK4 on NCC-mediated 22Na uptake, expressed as nmol/h per ...
(a) Effect of WNK4 on NCC-mediated 22Na uptake, expressed as nmol/h per oocyte. Uptake rates ± SEM of oocytes injected with cRNA encoding NCC, WNK4, NCC + WNK4, NCC + an antisense WNK4 (AS WNK4), NCC + SGK (an unrelated kinase), and water are shown. WNK4 alone has no effect on uptake. Coexpression with WNK4 significantly reduces NCC-mediated Na uptake. Neither antisense WNK4 nor SGK affects NCC activity. *Uptake significantly different from NCC injection alone; P < 0.001. (b) Immunoblot of oocytes probed with anti-WNK4 antibody: oocytes were injected with water or with cRNA encoding WNK4, WNK4 + NCC, or NCC alone. Only oocytes injected with WNK4 cRNA express WNK4 protein. For NCC, WNK4, and NCC + WNK4, there were 12 repetitions of each experiment (15–30 oocytes per experiment). For NCC + antisense WNK4 and NCC + SGK, there were four experiments.Relative molecular weights are shown in kDa. HCTZ, hydrochlorothiazide.
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