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The WNK signaling pathway and salt-sensitive hypertension

Hypertension Research volume 43, pages 733–743 (2020)Cite this article

Abstract

The distal nephron of the kidney has a central role in sodium and fluid homeostasis, and disruption of this homeostasis due to mutations of with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) causes pseudohypoaldosteronism type II (PHAII), an inherited hypertensive disease. WNK1 and WNK4 activate the NaCl cotransporter (NCC) at the distal convoluted tubule through oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline–alanine-rich kinase (SPAK), constituting the WNK–OSR1/SPAK–NCC phosphorylation cascade. The level of WNK protein is regulated through degradation by the CUL3–KLHL3 E3 ligase complex. In the normal state, the activity of WNK signaling in the kidney is physiologically regulated by sodium intake to maintain sodium homeostasis in the body. In patients with PHAII, however, because of the defective degradation of WNK kinases, NCC is constitutively active and not properly suppressed by a high salt diet, leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Importantly, recent studies have demonstrated that potassium intake, insulin, and TNFα are also physiological regulators of WNK signaling, suggesting that they contribute to the salt-sensitive hypertension associated with a low potassium diet, metabolic syndrome, and chronic kidney disease, respectively. Moreover, emerging evidence suggests that WNK signaling also has some unique roles in metabolic, cardiovascular, and immunological organs. Here, we review the recent literature and discuss the molecular mechanisms of the WNK signaling pathway and its potential as a therapeutic target.

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References

  1. Palmer LG, Schnermann J. Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol. 2015;10:676–87. https://doi.org/10.2215/CJN.12391213.

    Article  CAS  PubMed  Google Scholar 

  2. Simon DB, Nelson-Williams C, Johnson Bia M, Ellison D, Karet FE, Morey Molina A, et al. Gitelman’s variant of Barter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter. Nat Genet. 1996;12:24–30. https://doi.org/10.1038/ng0196-24.

    Article  CAS  PubMed  Google Scholar 

  3. Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. 1986;8:93–102. https://doi.org/10.1161/01.HYP.8.2.93.

    Article  CAS  PubMed  Google Scholar 

  4. Mayan H, Attar-Herzberg D, Shaharabany M, Holtzman EJ, Farfel Z. Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension. Nephrol Dial Transpl. 2007;23:492–6. https://doi.org/10.1093/ndt/gfm641.

    Article  CAS  Google Scholar 

  5. Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107–12. https://doi.org/10.1126/science.1062844.

    Article  CAS  PubMed  Google Scholar 

  6. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012;482:98–102. https://doi.org/10.1038/nature10814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012;44:456–60. https://doi.org/10.1038/ng.2218.

    Article  CAS  PubMed  Google Scholar 

  8. Xu B, English JM, Wilsbacher JL, Stippec S, Goldsmith EJ, Cobb MH. WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem. 2000;275:16795–801. https://doi.org/10.1074/jbc.275.22.16795.

    Article  CAS  PubMed  Google Scholar 

  9. Veríssimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene. 2001;20:5562–9. https://doi.org/10.1038/sj.onc.1204726.

    Article  PubMed  Google Scholar 

  10. Delaloy C, Lu J, Houot A-M, Disse-Nicodeme S, Gasc J-M, Corvol P, et al. Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform. Mol Cell Biol. 2003;23:9208–21. https://doi.org/10.1128/MCB.23.24.9208-9221.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. O’Reilly M. WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain. J Am Soc Nephrol. 2003;14:2447–56. https://doi.org/10.1097/01.ASN.0000089830.97681.3B.

    Article  CAS  PubMed  Google Scholar 

  12. Vidal-Petiot E, Cheval L, Faugeroux J, Malard T, Doucet A, Jeunemaitre X. et al. A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms. PLoS One. 2012;7:e37751. https://doi.org/10.1371/journal.pone.0037751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gong H, Tang Z, Yang Y, Sun L, Zhang W, Wang W, et al. A patient with pseudohypoaldosteronism type II caused by a novel mutation in WNK4 gene. Endocrine. 2008;33:230–4. https://doi.org/10.1007/s12020-008-9084-8.

    Article  CAS  PubMed  Google Scholar 

  14. Golbang AP, Murthy M, Hamad A, Liu C-H, Cope G, Van’t Hoff W, et al. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension. 2005;46:295–300. https://doi.org/10.1161/01.HYP.0000174326.96918.d6.

    Article  CAS  PubMed  Google Scholar 

  15. Yang S-S, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, et al. Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4D561A/+ knockin mouse model. Cell Metab. 2007;5:331–44. https://doi.org/10.1016/j.cmet.2007.03.009.

    Article  CAS  PubMed  Google Scholar 

  16. Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, et al. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013;3:858–68. https://doi.org/10.1016/j.celrep.2013.02.024.

    Article  CAS  PubMed  Google Scholar 

  17. Castañeda-Bueno M, Cervantes-Pérez LG, Vázquez N, Uribe N, Kantesaria S, Morla L, et al. Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci USA. 2012;109:7929–34. https://doi.org/10.1073/pnas.1200947109.

    Article  PubMed  Google Scholar 

  18. Takahashi D, Mori T, Nomura N, Khan MZH, Araki Y, Zeniya M, et al. WNK4 is the major WNK positively regulating NCC in the mouse kidney. Biosci Rep. 2014;34. https://doi.org/10.1042/BSR20140047.

  19. Vidal-Petiot E, Elvira-Matelot E, Mutig K, Soukaseum C, Baudrie V, Wu S, et al. WNK1-related familial hyperkalemic hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. Proc Natl Acad Sci USA. 2013;110:14366–71. https://doi.org/10.1073/pnas.1304230110.

    Article  PubMed  Google Scholar 

  20. Liu Z, Xie J, Wu T, Truong T, Auchus RJ, Huang C-L. Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models. Hum Mol Genet. 2011;20:855–66. https://doi.org/10.1093/hmg/ddq525.

    Article  CAS  PubMed  Google Scholar 

  21. Hadchouel J, Soukaseum C, Busst C, Zhou X-o, Baudrie V, Zurrer T, et al. Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension. Proc Natl Acad Sci USA. 2010;107:18109–14. https://doi.org/10.1073/pnas.1006128107.

    Article  PubMed  Google Scholar 

  22. Boyd-Shiwarski CR, Shiwarski DJ, Roy A, Namboodiri HN, Nkashama LJ, Xie J, et al. Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. Mol Biol Cell. 2018;29:499–509. https://doi.org/10.1091/mbc.E17-08-0529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Argaiz ER, Chavez-Canales M, Ostrosky-Frid M, Rodríguez-Gama A, Vázquez N, Gonzalez-Rodriguez X, et al. Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. Am J Physiol Ren Physiol. 2018;315:F734–45. https://doi.org/10.1152/ajprenal.00145.2018.

    Article  CAS  Google Scholar 

  24. Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem. 2005;280:42685–93. https://doi.org/10.1074/jbc.M510042200.

    Article  CAS  PubMed  Google Scholar 

  25. Vitari AC, Deak M, Morrice NA, Alessi DR. The WNK1 and WNK4 protein kinases that are mutated in Gordon’s hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J. 2005;391:17–24. https://doi.org/10.1042/BJ20051180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem. 2002;277:50812–9. https://doi.org/10.1074/jbc.M208108200.

    Article  CAS  PubMed  Google Scholar 

  27. Vitari AC, Thastrup J, Rafiqi FH, Deak M, Morrice NA, Karlsson HKR, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223–31. https://doi.org/10.1042/BJ20060220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zagórska A, Pozo-Guisado E, Boudeau J, Vitari AC, Rafiqi FH, Thastrup J, et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol. 2007;176:89–100. https://doi.org/10.1083/jcb.200605093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang S-S, Lo Y-F, Wu C-C, Lin S-W, Yeh C-J, Chu P, et al. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol. 2010;21:1868–77. https://doi.org/10.1681/ASN.2009121295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pacheco-Alvarez D, Cristóbal PS, Meade P, Moreno E, Vazquez N, Muñoz E, et al. The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J Biol Chem. 2006;281:28755–63. https://doi.org/10.1074/jbc.M603773200.

    Article  CAS  PubMed  Google Scholar 

  31. Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, et al. Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination. Biochem Biophys Res Commun. 2012;425:456–61. https://doi.org/10.1016/j.bbrc.2012.07.124.

    Article  CAS  PubMed  Google Scholar 

  32. Rafiqi FH, Zuber AM, Glover M, Richardson C, Fleming S, Jovanović S, et al. Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med. 2010;2:63–75. https://doi.org/10.1002/emmm.200900058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chiga M, Rafiqi FH, Alessi DR, Sohara E, Ohta A, Rai T, et al. Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. J Cell Sci. 2011;124:1391–5. https://doi.org/10.1242/jcs.084111.

    Article  CAS  PubMed  Google Scholar 

  34. Lai F, Orelli BJ, Till BG, Godley LA, Fernald AA, Pamintuan L, et al. Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene. Genomics. 2000;66:65–75. https://doi.org/10.1006/geno.2000.6181.

    Article  CAS  PubMed  Google Scholar 

  35. Ohta A, Schumacher F-R, Mehellou Y, Johnson C, Knebel A, Macartney TJ, et al. The CUL3-KLHL3 E3 ligase complex mutated in Gordon’s hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 2013;451:111–22. https://doi.org/10.1042/BJ20121903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci USA. 2013;110:7838–43. https://doi.org/10.1073/pnas.1304592110.

    Article  PubMed  Google Scholar 

  37. Wu G, Peng J-B. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett. 2013;587:1717–22. https://doi.org/10.1016/j.febslet.2013.04.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, et al. Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochem Biophys Res Commun. 2013;439:30–4. https://doi.org/10.1016/j.bbrc.2013.08.035.

    Article  CAS  PubMed  Google Scholar 

  39. Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, et al. Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. Hum Mol Genet. 2014;23:5052–60. https://doi.org/10.1093/hmg/ddu217.

    Article  CAS  PubMed  Google Scholar 

  40. Sasaki E, Susa K, Mori T, Isobe K, Araki Y, Inoue Y, et al. KLHL3 knockout mice reveal the physiological role of KLHL3 and the pathophysiology of pseudohypoaldosteronism type II caused by mutant KLHL3. Mol Cell Biol. 2017;37. https://doi.org/10.1128/MCB.00508-16.

  41. Araki Y, Rai T, Sohara E, Mori T, Inoue Y, Isobe K, et al. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene. Biol Open. 2015;4:1509–17. https://doi.org/10.1242/bio.013276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ferdaus MZ, Miller LN, Agbor LN, Saritas T, Singer JD, Sigmund CD, et al. Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. JCI Insight. 2017;2. https://doi.org/10.1172/jci.insight.96700.

  43. McCormick JA, Yang C-L, Zhang C, Davidge B, Blankenstein KI, Terker AS, et al. Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3. J Clin Invest. 2014;124:4723–36. https://doi.org/10.1172/JCI76126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yoshida S, Araki Y, Mori T, Sasaki E, Kasagi Y, Isobe K, et al. Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo. Clin Exp Nephrol. 2018;22:1251–7. https://doi.org/10.1007/s10157-018-1593-z.

    Article  CAS  PubMed  Google Scholar 

  45. Genschik P, Sumara I, Lechner E. The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications. EMBO J. 2013;32:2307–20. https://doi.org/10.1038/emboj.2013.173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schumacher F, Siew K, Zhang J, Johnson C, Wood N, Cleary SE, et al. Characterisation of the Cullin‐3 mutation that causes a severe form of familial hypertension and hyperkalaemia. EMBO Mol Med. 2015;7:1285–306. https://doi.org/10.15252/emmm.201505444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pintard L, Kurz T, Glaser S, Willis JH, Peter M, Bowerman B. Neddylation and deneddylation of CUL-3 is required to target MEI-1/Katanin for degradation at the meiosis-to-mitosis transition in C. elegans. Curr Biol. 2003;13:911–21. https://doi.org/10.1016/s0960-9822(03)00336-1.

    Article  CAS  PubMed  Google Scholar 

  48. Cornelius RJ, Zhang C, Erspamer KJ, Agbor LN, Sigmund CD, Singer JD, et al. Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension. Am J Physiol Physiol. 2018;315:F1006–18. https://doi.org/10.1152/ajprenal.00602.2017.

    Article  CAS  Google Scholar 

  49. Cornelius RJ, Si J, Cuevas CA, Nelson JW, Gratreak BDK, Pardi R, et al. Renal COP9 signalosome deficiency alters CUL3-KLHL3-WNK signaling pathway. J Am Soc Nephro. 2018. https://doi.org/10.1681/ASN.2018030333.

  50. Abdel Khalek W, Rafael C, Loisel-Ferreira I, Kouranti I, Clauser E, Hadchouel J, et al. Severe arterial hypertension from cullin 3 mutations is caused by both renal and vascular effects. J Am Soc Nephrol. 2019;30:811–23. https://doi.org/10.1681/ASN.2017121307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Agbor LN, Ibeawuchi S-RC, Hu C, Wu J, Davis DR, Keen HL, et al. Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism. JCI Insight. 2016;1. https://doi.org/10.1172/jci.insight.91015.

  52. Susa K, Sohara E, Takahashi D, Okado T, Rai T, Uchida S. WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3. Biochem Biophys Res Commun. 2017;491:727–32. https://doi.org/10.1016/j.bbrc.2017.07.121.

    Article  CAS  PubMed  Google Scholar 

  53. Kotchen TA, Cowley AW, Frohlich ED. Salt in Health and Disease—a delicate balance. N Engl J Med. 2013;368:1229–37. https://doi.org/10.1056/NEJMra1212606.

    Article  CAS  PubMed  Google Scholar 

  54. Hall JE. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation. 2016;133:894–906. https://doi.org/10.1161/CIRCULATIONAHA.115.018526.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chiga M, Rai T, Yang S-S, Ohta A, Takizawa T, Sasaki S, et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008;74:1403–9. https://doi.org/10.1038/ki.2008.451.

    Article  CAS  PubMed  Google Scholar 

  56. San-Cristobal P, Pacheco-Alvarez D, Richardson C, Ring AM, Vazquez N, Rafiqi FH, et al. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc Natl Acad Sci USA. 2009;106:4384–9. https://doi.org/10.1073/pnas.0813238106.

    Article  PubMed  Google Scholar 

  57. Talati G, Ohta A, Rai T, Sohara E, Naito S, Vandewalle A, et al. Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney. Biochem Biophys Res Commun. 2010;393:844–8. https://doi.org/10.1016/j.bbrc.2010.02.096.

    Article  CAS  PubMed  Google Scholar 

  58. van der Lubbe N, Lim CH, Fenton RA, Meima ME, Jan Danser AH, Zietse R, et al. Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. Kidney Int. 2011;79:66–76. https://doi.org/10.1038/ki.2010.290.

    Article  CAS  PubMed  Google Scholar 

  59. Cheng L, Poulsen SB, Wu Q, Esteva-Font C, Olesen ETB, Peng L, et al. Rapid aldosterone-mediated signaling in the DCT increases activity of the thiazide-sensitive NaCl cotransporter. J Am Soc Nephrol. 2019;30:1454–70. https://doi.org/10.1681/ASN.2018101025.

    Article  PubMed  Google Scholar 

  60. Wolley MJ, Wu A, Xu S, Gordon RD, Fenton RA, Stowasser M. In primary aldosteronism, mineralocorticoids influence exosomal sodium-chloride cotransporter abundance. J Am Soc Nephrol. 2017;28:56–63. https://doi.org/10.1681/ASN.2015111221.

    Article  CAS  PubMed  Google Scholar 

  61. Czogalla J, Vohra T, Penton D, Kirschmann M, Craigie E, Loffing J. The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion. Pflügers Arch—Eur J Physiol. 2016;468:849–58. https://doi.org/10.1007/s00424-016-1798-5.

    Article  CAS  Google Scholar 

  62. Terker AS, Yarbrough B, Ferdaus MZ, Lazelle RA, Erspamer KJ, Meermeier NP, et al. Direct and indirect mineralocorticoid effects determine distal salt transport. J Am Soc Nephrol. 2016;27:2436–45. https://doi.org/10.1681/ASN.2015070815.

    Article  CAS  PubMed  Google Scholar 

  63. Shibata S, Arroyo JP, Castaneda-Bueno M, Puthumana J, Zhang J, Uchida S, et al. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. Proc Natl Acad Sci USA. 2014;111:15556–61. https://doi.org/10.1073/pnas.1418342111.

    Article  CAS  PubMed  Google Scholar 

  64. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. PURE investigators. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med. 2014;371:601–11. https://doi.org/10.1056/NEJMoa1311989.

    Article  CAS  PubMed  Google Scholar 

  65. Mente A, O’Donnell M, Rangarajan S, McQueen M, Dagenais G, Wielgosz A, et al. Urinary sodium excretion, blood pressure, cardiovascular disease, and mortality: a community-level prospective epidemiological cohort study. Lancet. 2018;392:496–506. https://doi.org/10.1016/S0140-6736(18)31376-X.

    Article  PubMed  Google Scholar 

  66. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med. 2014;371:612–23. https://doi.org/10.1056/NEJMoa1311889.

    Article  CAS  PubMed  Google Scholar 

  67. Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, et al. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab. 2015;21:39–50. https://doi.org/10.1016/j.cmet.2014.12.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Terker AS, Zhang C, Erspamer KJ, Gamba G, Yang C-L, Ellison DH. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int. 2016;89:127–34. https://doi.org/10.1038/ki.2015.289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wade JB, Liu J, Coleman R, Grimm PR, Delpire E, Welling PA. SPAK-mediated NCC regulation in response to low-K+ diet. Am J Physiol Ren Physiol. 2015;308:F923–31. https://doi.org/10.1152/ajprenal.00388.2014.

    Article  CAS  Google Scholar 

  70. Ferdaus MZ, Barber KW, López-Cayuqueo KI, Terker AS, Argaiz ER, Gassaway BM, et al. SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule. J Physiol. 2016;594:4945–66. https://doi.org/10.1113/JP272311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vitzthum H, Seniuk A, Schulte LH, Müller ML, Hetz H, Ehmke H. Functional coupling of renal K + and Na + handling causes high blood pressure in Na + replete mice. J Physiol. 2014;592:1139–57. https://doi.org/10.1113/jphysiol.2013.266924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Castañeda-Bueno M, Cervantes-Perez LG, Rojas-Vega L, Arroyo-Garza I, Vázquez N, Moreno E, et al. Modulation of NCC activity by low and high K + intake: insights into the signaling pathways involved. Am J Physiol Physiol. 2014;306:F1507–19. https://doi.org/10.1152/ajprenal.00255.2013.

    Article  CAS  Google Scholar 

  73. Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ. Chloride Sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal. 2014;7:ra41. https://doi.org/10.1126/scisignal.2005050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang M-X, Cuevas CA, Su X-T, Wu P, Gao Z-X, Lin D-H, et al. Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel. Kidney Int. 2018;93:893–902. https://doi.org/10.1016/j.kint.2017.10.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wu P, Gao Z-X, Zhang D-D, Su X-T, Wang W-H, Lin D-H. Deletion of Kir5.1 impairs renal ability to excrete potassium during increased dietary potassium intake. J Am Soc Nephrol. 2019;30:1425–38. https://doi.org/10.1681/ASN.2019010025.

    Article  PubMed  Google Scholar 

  76. Nomura N, Shoda W, Wang Y, Mandai S, Furusho T, Takahashi D, et al. Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney. Biosci Rep. 2018;38. https://doi.org/10.1042/BSR20171243.

  77. Chen J-C, Lo Y-F, Lin Y-W, Lin S-H, Huang C-L, Cheng C-J. WNK4 kinase is a physiological intracellular chloride sensor. Proc Natl Acad Sci USA. 2019;116:4502–7. https://doi.org/10.1073/pnas.1817220116.

    Article  CAS  PubMed  Google Scholar 

  78. Nomura N, Shoda W, Uchida S. Clinical importance of potassium intake and molecular mechanism of potassium regulation. Clin Exp Nephrol. 2019;23:1175–80. https://doi.org/10.1007/s10157-019-01766-x.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Rengarajan S, Lee DH, Oh YT, Delpire E, Youn JH, McDonough AA. Increasing plasma [K +] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis. Am J Physiol Physiol. 2014;306:F1059–68. https://doi.org/10.1152/ajprenal.00015.2014.

    Article  CAS  Google Scholar 

  80. Shoda W, Nomura N, Ando F, Mori Y, Mori T, Sohara E, et al. Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake. Kidney Int. 2017;91:402–11. https://doi.org/10.1016/j.kint.2016.09.001.

    Article  CAS  PubMed  Google Scholar 

  81. Penton D, Moser S, Wengi A, Czogalla J, Rosenbaek LL, Rigendinger F, et al. Protein phosphatase 1 inhibitor–1 mediates the cAMP-dependent stimulation of the renal NaCl cotransporter. J Am Soc Nephrol. 2019;30:737–50. https://doi.org/10.1681/ASN.2018050540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen J, Gu D, Huang J, Rao DC, Jaquish CE, Hixson JE GenSalt Collaborative Research Group, et al. Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study. Lancet. 2009;373:829–35. https://doi.org/10.1016/S0140-6736(09)60144-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chávez-Canales M, Arroyo JP, Ko B, Vázquez N, Bautista R, Castañeda-Bueno M. et al. Insulin increases the functional activity of the renal NaCl cotransporter. J Hypertens. 2013;31:303–11. https://doi.org/10.1097/HJH.0b013e32835bbb83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Komers R, Rogers S, Oyama TT, Xu B, Yang C-L, McCormick J, et al. Enhanced phosphorylation of Na(+)-Cl- co-transporter in experimental metabolic syndrome: role of insulin. Clin Sci. 2012;123:635–47. https://doi.org/10.1042/CS20120003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sohara E, Rai T, Yang S-S, Ohta A, Naito S, Chiga M. et al. Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney. PLoS One. 2011;6:e24277. https://doi.org/10.1371/journal.pone.0024277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, et al. Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension. 2012;60:981–90. https://doi.org/10.1161/HYPERTENSIONAHA.112.201509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ishizawa K, Wang Q, Li J, Xu N, Nemoto Y, Morimoto C, et al. Inhibition of sodium glucose cotransporter 2 attenuates the dysregulation of Kelch-Like 3 and NaCl cotransporter in obese diabetic mice. J Am Soc Nephrol. 2019;30:782–94. https://doi.org/10.1681/ASN.2018070703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yoshizaki Y, Mori Y, Tsuzaki Y, Mori T, Nomura N, Wakabayashi M, et al. Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3. Biochem Biophys Res Commun. 2015;467:229–34. https://doi.org/10.1016/j.bbrc.2015.09.184.

    Article  CAS  PubMed  Google Scholar 

  89. Punzi HA, Punzi CF. Metabolic issues in the antihypertensive and lipid-lowering heart attack trial study. Curr Hypertens Rep. 2004;6:106–10. https://doi.org/10.1007/s11906-004-0084-7.

    Article  PubMed  Google Scholar 

  90. Mori T, Kikuchi E, Watanabe Y, Fujii S, Ishigami-Yuasa M, Kagechika H, et al. Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy. Biochem J. 2013;455:339–45. https://doi.org/10.1042/BJ20130597.

    Article  CAS  PubMed  Google Scholar 

  91. Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, et al. Discovery of novel SPAK inhibitors that block WNK kinase signaling to cation chloride transporters. J Am Soc Nephrol. 2015;26:1525–36. https://doi.org/10.1681/ASN.2014060560.

    Article  CAS  PubMed  Google Scholar 

  92. Yamada K, Park H-M, Rigel DF, DiPetrillo K, Whalen EJ, Anisowicz A, et al. Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016;12:896–8. https://doi.org/10.1038/nchembio.2168.

    Article  CAS  PubMed  Google Scholar 

  93. Hashimoto H, Nomura N, Shoda W, Isobe K, Kikuchi H, Yamamoto K, et al. Metformin increases urinary sodium excretion by reducing phosphorylation of the sodium-chloride cotransporter. Metabolism. 2018;85:23–31. https://doi.org/10.1016/j.metabol.2018.02.009.

    Article  CAS  PubMed  Google Scholar 

  94. Townsend RR, Taler SJ. Management of hypertension in chronic kidney disease. Nat Rev Nephrol. 2015;11:555–63. https://doi.org/10.1038/nrneph.2015.114.

    Article  PubMed  Google Scholar 

  95. Kamat NV, Thabet SR, Xiao L, Saleh MA, Kirabo A, Madhur MS, et al. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice. Hypertension. 2015;65:569–76. https://doi.org/10.1161/HYPERTENSIONAHA.114.04975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK, Giani JF, Nguyen MTX, Riquier-Brison AD, et al. The absence of intrarenal ACE protects against hypertension. J Clin Invest. 2013;123:2011–23. https://doi.org/10.1172/JCI65460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kobayashi R, Wakui H, Azushima K, Uneda K, Haku S, Ohki K, et al. An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. Kidney Int. 2017;91:1115–25. https://doi.org/10.1016/j.kint.2016.10.035.

    Article  CAS  PubMed  Google Scholar 

  98. Rucker AJ, Rudemiller NP, Crowley SD. Salt, hypertension, and immunity. Annu Rev Physiol. 2018;80:283–307. https://doi.org/10.1146/annurev-physiol-021317-121134.

    Article  CAS  PubMed  Google Scholar 

  99. Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med. 2018;215:21–33. https://doi.org/10.1084/jem.20171773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–60. https://doi.org/10.1084/jem.20070657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang J, Patel MB, Griffiths R, Mao A, Song Y, Karlovich NS, et al. Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension. Hypertension. 2014;64:1275–81. https://doi.org/10.1161/HYPERTENSIONAHA.114.03863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yoshida S, Takeuchi T, Kotani T, Yamamoto N, Hata K, Nagai K, et al. Infliximab, a TNF-α inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients. J Hum Hypertens. 2014;28:165–9. https://doi.org/10.1038/jhh.2013.80.

    Article  CAS  PubMed  Google Scholar 

  103. Furusho T, Sohara E, Mandai S, Kikuchi H, Takahashi N, Fujimaru T, et al. Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease. Kidney Int. 2020;97:713–27. https://doi.org/10.1016/j.kint.2019.11.021.

    Article  CAS  PubMed  Google Scholar 

  104. Roy A, Al-Qusairi L, Donnelly BF, Ronzaud C, Marciszyn AL, Gong F, et al. Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action. J Clin Invest. 2015;125:3433–48. https://doi.org/10.1172/JCI75245.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Takahashi D, Mori T, Sohara E, Tanaka M, Chiga M, Inoue Y, et al. WNK4 is an adipogenic factor and its deletion reduces diet-induced obesity in mice. EBioMedicine. 2017;18:118–27. https://doi.org/10.1016/j.ebiom.2017.03.011.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Torre-Villalvazo I, Cervantes-Pérez LG, Noriega LG, Jiménez JV, Uribe N, Chávez-Canales M, et al. Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity. Am J Physiol Metab. 2018;314:E53–65. https://doi.org/10.1152/ajpendo.00108.2017.

    Article  CAS  Google Scholar 

  107. Mandai S, Mori T, Nomura N, Furusho T, Arai Y, Kikuchi H, et al. WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4. Sci Rep. 2018;8. https://doi.org/10.1038/s41598-018-27414-0.

  108. Köchl R, Thelen F, Vanes L, Brazão TF, Fountain K, Xie J, et al. WNK1 kinase balances T cell adhesion versus migration in vivo. Nat Immunol. 2016;17:1075–83. https://doi.org/10.1038/ni.3495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, et al. Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway. Nat Cell Biol. 2019;21:1532–43. https://doi.org/10.1038/s41556-019-0431-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dbouk HA, Weil LM, Perera GKS, Dellinger MT, Pearson G, Brekken RA, et al. Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proc Natl Acad Sci USA. 2014;111:15999–6004. https://doi.org/10.1073/pnas.1419057111.

    Article  CAS  PubMed  Google Scholar 

  111. Xie J, Yoon J, Yang S-S, Lin S-H, Huang C-L. WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. J Biol Chem. 2013;288:8566–74. https://doi.org/10.1074/jbc.M113.451575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gallolu Kankanamalage S, Karra AS, Cobb MH. WNK pathways in cancer signaling networks. Cell Commun Signal. 2018;16:72. https://doi.org/10.1186/s12964-018-0287-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) [Grant Numbers: 25221306–00, 19H01049, 18K19534, 16H05314, and 19H03672], a Health Labor Science Research Grant from the Ministry of Health, Labor, and Welfare, AMED under Grant Number JP18ek0109304, and grants from the Yukiko Ishibashi Foundation and the Salt Science Research Foundation (1925).

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  1. Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Taisuke Furusho, Shinichi Uchida & Eisei Sohara

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Furusho, T., Uchida, S. & Sohara, E. The WNK signaling pathway and salt-sensitive hypertension. Hypertens Res 43, 733–743 (2020). https://doi.org/10.1038/s41440-020-0437-x

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