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Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

Abstract

The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4WT) or PHAII mutant (TgWnk4PHAII) Wnk4 is changed in opposite directions: TgWnk4PHAII mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4WT mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4PHAII mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.

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Figure 1: Production of modified BAC transgenes.
Figure 2: Wnk4 BAC transgenes and their expression in mice.
Figure 3: High and low blood pressure in Tg(Wnk4PHAII) and Tg(Wnk4WT) mice.
Figure 4: Altered electrolyte homeostasis in Tg(Wnk4PHAII) and Tg(Wnk4WT) mice.
Figure 5: Altered DCT morphology of Tg(Wnk4WT) and Tg(Wnk4PHAII) mice.
Figure 6: Expression of ROMK in collecting duct of wild-type and Tg(Wnk4PHAII) mice.
Figure 7: Correction of DCT hyperplasia in Tg(Wnk4PHAII) by NCC deficiency.
Figure 8: Interaction of Wnk4WT and Wnk4PHAII.

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Acknowledgements

This work was supported in part by a Human Frontiers Science Program (HFSP) long-term fellowship (M.D.L.; LT00606/2002) and a US National Institutes of Health Specialized Center of Research in Hypertension (R.P.L., D.S.G.). We thank C. Canessa for the anti-β-ENaC and J. Wade and M. Knepper for anti-NCC. We thank A. Louvi and X. Tian for help with cardiac perfusion, C. Spilianakis for the GAPDH BAC, D. Sakkas for help with statistical analysis and H. Qin, K. Choate, K. Finberg and F. Wilson for discussion. We also thank R. Pongratz and L. Rosenthal for electrolyte measurements and S. Mentone for tissue sections.

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Correspondence to Richard P Lifton.

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Supplementary information

Supplementary Fig. 1

Immunostaining for Wnk4, THP and Ncc in kidney sections of a Tg(Wnk4PHAII) mouse. (PDF 700 kb)

Supplementary Fig. 2

Immunostaining for Ncc. (PDF 620 kb)

Supplementary Fig. 3

Immunostaining for Romk and β-ENaC. (PDF 1162 kb)

Supplementary Fig. 4

Quantitative RT-PCR. (PDF 142 kb)

Supplementary Table 1

Blood pressure. (PDF 57 kb)

Supplementary Table 2

Serum electrolytes. (PDF 63 kb)

Supplementary Table 3

Urine electrolytes. (PDF 36 kb)

Supplementary Table 4

PCR primers. (PDF 27 kb)

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Lalioti, M., Zhang, J., Volkman, H. et al. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet 38, 1124–1132 (2006). https://doi.org/10.1038/ng1877

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