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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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.
The authors declare no competing financial interests.
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