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WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

Nature Genetics volume 35, pages 372–376 (2003)Cite this article

Abstract

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis1. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration (refs. 2,3). Positional cloning implicated the serine-threonine kinase WNK4 in this process4; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII5) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition6. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.

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Figure 1: WNK4 inhibits ROMK-mediated K+ currents.
Figure 2: WNK4 reduces surface expression of ROMK.
Figure 3: WNK4 inhibits ROMK through clathrin-dependent endocytosis and interacts with the C terminus of ROMK.
Figure 4: Mutant forms of WNK4 that cause PHAII increase inhibition of ROMK.
Figure 5: Role of WNK4 in regulating the balance between renal NaCl reabsorption and K+ secretion.

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Acknowledgements

We thank I. Giménez, P. Zhang and members of the laboratory of W. Boron for harvest of X. laevis oocytes, and P.Z. Svigals for technical assistance. This work was supported by a Specialized Center of Research Grant in Hypertension (R.P.L.) and an Interactive Program Grant (S.C.H.) from the US National Institutes of Health. K.T.K. is recipient of a Howard Hughes Medical Institute Medical Student Research Fellowship. M.D.L. is a recipient of a Human Frontiers Long Term Fellowship. R.P.L. is an Investigator of the Howard Hughes Medical Institute.

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  1. Kristopher T Kahle and Frederick H Wilson: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, 300 Cedar Street, TAC S-341D

    Kristopher T Kahle, Frederick H Wilson, Maria D Lalioti, Alicia K Rapson & Richard P Lifton

  2. Departments of Genetics, Medicine, Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Kristopher T Kahle, Frederick H Wilson, Maria D Lalioti, Alicia K Rapson & Richard P Lifton

  3. Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Qiang Leng, Anthony D O'Connell, Ke Dong, Gordon G MacGregor, Gerhard Giebisch & Steven C Hebert

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Correspondence to Richard P Lifton.

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Kahle, K., Wilson, F., Leng, Q. et al. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet 35, 372–376 (2003). https://doi.org/10.1038/ng1271

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