Abstract
Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na(+)Cl(-) cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K(+) secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4(-/-)). WNK4 mRNA and protein expression were absent in WNK4(-/-) mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4(+/+) but not WNK4(-/-) mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K(+) diet, was impaired in WNK4(-/-) mice.
Highlights
Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4)
An elegant set of renal transplant experiments between wild-type and angiotensin II (AngII) type 1 (AT1) receptor-knockout mice has revealed that arterial hypertension induced by AngII requires the presence of AT1 receptors in the kidney but not in any other tissue [1] and that hypertension mostly is the consequence of an increase in renal salt reabsorption [2]
Numerous studies in Xenopus laevis oocytes, Cos-7 cells, HEK-293 cells, and BAC transgenic mice have shown that WNK4 is a negative modulator of NCC activity that becomes an activator when its primary structure is changed by the Pseudohypoaldosteronism type II (PHAII)- type mutations
Summary
Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). In addition to increasing the activity of the NCC, the PHAIImutant WNK4 increases activity of the apical epithelial sodium channel (ENaC) [15] and distal paracellular chloride transport (because of its action on claudins) [16, 17] while strongly inhibiting the renal outer medullary potassium channel (ROMK) [18] The combination of these effects induces salt reabsorption and prevents K+ secretion, mimicking what occurs in the distal nephron during a low-salt diet or hypovolemia, conditions characterized by the activation of the RAAS. We proposed that PHAII-type mutations confer a gain of function to WNK4 that mimics the effect produced by AngII upon the WNK4– SPAK–NCC pathway [19] This hypothesis was supported by observations made in Xenopus laevis oocytes and murine distal convoluted tubule (mpkDCT) cells in which AngII induces a WNK4-SPAK–dependent increase in NCC phosphorylation and activity that can be prevented with the specific AT1 receptor blocker, losartan [19]. The goal of the present study was to Author contributions: M.C.-B., L.G.C.-P., S.K., L.M., N.A.B., A.D., D.R.A., and G.G. designed research; M.C.-B., L.G.C.-P., N.V., N.U., S.K., and L.M. performed research; S.K. contributed new reagents/analytic tools; M.C.-B., L.G.C.-P., N.V., N.U., L.M., N.A.B., A.D., D.R.A., and
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
