Abstract
Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca(2+)-dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca(2+) influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca(2+) influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.
Highlights
Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension
Deletion of the Na+Cl− cotransporter (NCC) reversed most of the phenotypes seen in the transgenic mice harboring the PHAII-causing WNK4 mutants [5], which indicated that aberrant regulation of NCC by the mutant WNK4 is critically involved in the pathogenesis of PHAII
Depletion of WNK4 in vascular smooth muscle cells (VSMCs) significantly increased Ba2+ influx that was largely abolished by knockdown of native transient receptor potential canonical 3 (TRPC3) (Fig. 1 B and C). siRNA against TRPC3 had no effect on the expression of TRPC1 and TRPC6 (Fig. S1), which are known to induce G-protein-coupled receptors (GPCRs)-mediated [Ca2+]i increase in VSMCs [12,13,14]
Summary
Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. Deletion of the Na+Cl− cotransporter (NCC) reversed most of the phenotypes seen in the transgenic mice harboring the PHAII-causing WNK4 mutants [5], which indicated that aberrant regulation of NCC by the mutant WNK4 is critically involved in the pathogenesis of PHAII This finding led to the suggestion that increased Na+ in systemic fluids by the altered NCC activity is associated with elevated blood pressure [7,8,9,10]. We report a molecular mechanism by which WNK4 regulates TRPC3 activity to determine vascular tone and its ablation by WNK4 mutations associated with hypertension These results shed light on the previously undescribed signal pathway of WNK4related hypertension, and provide important therapeutic strategies to correct aberrant blood pressure
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