Skip to main content
SpringerLink
Log in

Familial Hyperkalemic Hypertension (FHHt)

  • Reference work entry
  • First Online:
Hydro Saline Metabolism

Part of the book series: Endocrinology ((ENDOCR))

  • 151 Accesses

Abstract

Familial Hyperkalemic Hypertension (FHHt) syndrome, also known as Gordon syndrome or Pseudohypoaldosteronism type II, is a very rare genetic form of hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis, low renin and a normal GFR. These disorders are all corrected by thiazide diuretics that inhibit the Na+-Cl− NCC cotransporter expressed in the distal convoluted tubule of the nephron. The sensitivity of FHHt patients to thiazide diuretics strongly suggested that FHHt is caused by an excessive sodium-chloride reabsorption by NCC. However, no mutations in the SLC12A3 gene, encoding NCC, were discovered in FHHt patients. Mutations were first identified in the genes encoding the serine-threonine kinases WNK1 and WNK4 [With No (K) lysine] and then in genes encoding components of a ubiquitin ligase complex, cullin-3 (CUL3), and Kelch-like family member 3 (KLHL3). Subsequent in vitro and in vivo studies have demonstrated that NCC is stimulated by a signaling pathway activated by WNK1 and WNK4, which are themselves targeted for proteosomal degradation by the Cul3-KLHL3 complex.

Therefore, the study of this very rare and easily treatable syndrome has led to the discovery of a new, unsuspected molecular pathway responsible for the regulation of ion handling in the distal nephron. In this chapter, we will describe how thus pathway was discovered and how these studies have allowed to understand how sodium reabsorption by the distal nephron is modulated by both sodium and potassium intakes to maintain blood pressure and plasma potassium balance.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 379.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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(5):811–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Achard J-M, Disse-Nicodeme S, Fiquet-Kempf B, Jeunemaitre X. Phenotypic and genetic heterogeneity of familial hyperkalaemic hypertension (Gordon syndrome). Clin Exp Pharmacol Physiol. 2001;28(12):1048–52.

    Article  CAS  PubMed  Google Scholar 

  • Adams J, Kelso R, Cooley L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol. 2000;10(1):17–24.

    Article  CAS  PubMed  Google Scholar 

  • AlAmri MA, Kadri H, Alderwick LJ, Simpkins NS, Mehellou Y. Rafoxanide and closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C terminal domains. ChemMedChem. 2017;12(9):639–45.

    Article  CAS  PubMed  Google Scholar 

  • AlAmri MA, Kadri H, Alderwick LJ, Jeeves M, Mehellou Y. The photosensitising clinical agent verteporfin is an inhibitor of SPAK and OSR1 kinases. Chembiochem. 2018;19(19):2072–80.

    Article  CAS  PubMed  Google Scholar 

  • Andérica-Romero AC, Escobar L, Padilla-Flores T, Pedraza-Chaverri J. Insights in cullin 3/WNK4 and its relationship to blood pressure regulation and electrolyte homeostasis. Cell Signal. 2014;26(6):1166–72.

    Article  PubMed  Google Scholar 

  • Argaiz ER, Gamba G. On the molecular mechanism of renal salt excretion modulation by extracellular potassium. J Physiol. 2016;594(21):6071–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnold JE, Healy JK. Hyperkalemia, hypertension and systemic acidosis without renal failure associated with a tubular defect in potassium excretion. Am J Med. 1969;47(3):461–72.

    Article  CAS  PubMed  Google Scholar 

  • Bastani B, Purcell H, Hemken P, Trigg D, Gluck S. Expression and distribution of renal vacuolar proton-translocating adenosine triphosphatase in response to chronic acid and alkali loads in the rat. J Clin Invest. 1991;88(1):126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bazúa-Valenti S, Gamba G. Revisiting the NaCl cotransporter regulation by with-no-lysine kinases. Am J Physiol Cell Physiol. 2015;308(10):C779–91.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bazúa-Valenti S, Chávez-Canales M, Rojas-Vega L, González-Rodríguez X, Vázquez N, Rodríguez-Gama A, et al. The effect of WNK4 on the Na+–Cl− cotransporter is modulated by intracellular chloride. J Am Soc Nephrol. 2015;26(8):1781–6.

    Article  PubMed  Google Scholar 

  • Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med. 2009;360(19):1960–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boettger T, Hübner CA, Maier H, Rust MB, Beck FX, Jentsch TJ. Deafness and renal tubular acidosis in mice lacking the K–Cl co-transporter Kcc4. Nature. 2002;416(6883):874–8.

    Article  CAS  PubMed  Google Scholar 

  • 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(7383):98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brautbar N, Levi J, Rosler A, Leitesdorf E, Djaldeti M, Epstein M, et al. Familial hyperkalemia, hypertension, and hyporeninemia with normal aldosterone levels. A tubular defect in potassium handling. Arch Intern Med. 1978;138(4):607–10.

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A. 2012;109(20):7929–34.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 Renal Physiol. 2014;306(12):F1507–19.

    Article  PubMed  PubMed Central  Google Scholar 

  • Castañeda-Bueno M, Arroyo JP, Zhang J, Puthumana J, Yarborough O, Shibata S, et al. Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4. Proc Natl Acad Sci U S A. 2017;114(5):E879–86.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chávez-Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco-Alvarez D, Vidal-Petiot E, et al. WNK-SPAK-NCC cascade revisited novelty and significance. Hypertension. 2014;64(5):1047–53.

    Article  PubMed  Google Scholar 

  • 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 U S A. 2019;116(10):4502–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cope GA, Suh GSB, Aravind L, Schwarz SE, Zipursky SL, Koonin EV, et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science. 2002;298(5593):608–11.

    Article  CAS  PubMed  Google Scholar 

  • Cope G, Murthy M, Golbang AP, Hamad A, Liu C-H, Cuthbert AW, et al. WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. J Am Soc Nephrol. 2006;17(7):1867–74.

    Article  CAS  PubMed  Google Scholar 

  • de Seigneux S, Malte H, Dimke H, Frøkiær J, Nielsen S, Frische S. Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule. Am J Physiol Renal Physiol. 2007;292(4):F1256–66.

    Article  PubMed  Google Scholar 

  • Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, et al. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression. EMBO J. 2001;20(24):7052–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(24):9208–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Disse-Nicodème S, Achard J-M, Desitter I, Houot A-M, Fournier A, Corvol P, et al. A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Am J Hum Genet. 2000;67(2):302–10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Disse-Nicodeme S, Desitter I, Fiquet-Kempf B, Houot AM, Stern N, Delahousse M, et al. Genetic heterogeneity of familial hyperkalaemic hypertension. J Hypertens. 2001;19(11):1957–64.

    Article  CAS  PubMed  Google Scholar 

  • Dowd BFX, Forbush B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1). J Biol Chem. 2003;278(30):27347–53.

    Article  CAS  PubMed  Google Scholar 

  • Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell. 2008;134(6):995–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eaton DC, Malik B, Bao H-F, Yu L, Jain L. Regulation of epithelial sodium channel trafficking by ubiquitination. Proc Am Thorac Soc. 2010;7(1):54–64.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ecelbarger CA, Terris J, Frindt G, Echevarria M, Marples D, Nielsen S, et al. Aquaporin-3 water channel localization and regulation in rat kidney. Am J Physiol. 1995;269(5 Pt 2):F663–72.

    CAS  PubMed  Google Scholar 

  • Erlich PM, Cui J, Chazaro I, Farrer LA, Baldwin CT, Gavras H, et al. Genetic variants of WNK4 in Whites and African Americans with hypertension. Hypertension. 2003;41(6):1191–5.

    Article  CAS  PubMed  Google Scholar 

  • Fang L, Garuti R, Kim B-Y, Wade JB, Welling PA. The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidney. J Clin Invest. 2009;119(11):3278–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Féraille E, Doucet A. Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control. Physiol Rev. 2001;81(1):345–418.

    Article  PubMed  Google Scholar 

  • Ferdaus MZ, McCormick JA. The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy. Am J Physiol Renal Physiol. 2016;310(11):F1389–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedel P, Kahle KT, Zhang J, Hertz N, Pisella LI, Buhler E, et al. WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Sci Signal. 2015;8(383):ra65.

    Article  PubMed  Google Scholar 

  • Frindt G, Palmer LG. Low-conductance K channels in apical membrane of rat cortical collecting tubule. Am J Physiol. 1989;256(1 Pt 2):F143–51.

    CAS  PubMed  Google Scholar 

  • Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S. Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature. 1993;361(6412):549–52.

    Article  CAS  PubMed  Google Scholar 

  • Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85(2):423–93.

    Article  CAS  PubMed  Google Scholar 

  • Gereda JE, Bonilla-Felix M, Kalil B, Dewitt SJ. Neonatal presentation of Gordon syndrome. J Pediatr. 1996;129(4):615–7.

    Article  CAS  PubMed  Google Scholar 

  • Golbang AP, Murthy M, Hamad A, Liu C-H, Cope G, Hoff WV, 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(2):295–300.

    Article  CAS  PubMed  Google Scholar 

  • Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. 1986;8(2):93–102.

    Article  CAS  PubMed  Google Scholar 

  • Gordon RD. Heterogeneous hypertension. Nat Genet. 1995;11(1):6–9.

    Article  CAS  PubMed  Google Scholar 

  • Gordon RD, Hodsman GP. The syndrome of hypertension and hyperkalaemia without renal failure: long term correction by thiazide diuretic. Scott Med J. 1986;31(1):43–4.

    Article  CAS  PubMed  Google Scholar 

  • Gordon RD, Geddes RA, Pawsey CG, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas Ann Med. 1970;19(4):287–94.

    Article  CAS  PubMed  Google Scholar 

  • Grimm PR, Taneja TK, Liu J, Coleman R, Chen Y-Y, Delpire E, et al. SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem. 2012;287(45):37673–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimm PR, Lazo-Fernandez Y, Delpire E, Wall SM, Dorsey SG, Weinman EJ, et al. Integrated compensatory network is activated in the absence of NCC phosphorylation. J Clin Invest. 2015;125(5):2136–50.

    Article  PubMed  PubMed Central  Google Scholar 

  • Grimm PR, Coleman R, Delpire E, Welling PA. Constitutively active SPAK causes hyperkalemia by activating NCC and remodeling distal tubules. J Am Soc Nephrol. 2017;28(9):2597–606.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gupta VA, Beggs AH. Kelch proteins: emerging roles in skeletal muscle development and diseases. Skelet Muscle. 2014;4:11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hadchouel J, Soukaseum C, Büsst C, Zhou X, Baudrie V, Zürrer 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 U S A. 2010;107(42):18109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Y, Fan X, Sun K, Wang X, Wang Y, Chen J, et al. Hypertension associated polymorphisms in WNK1/WNK4 are not associated with hydrochlorothiazide response. Clin Biochem. 2011;44(13):1045–9.

    Article  CAS  PubMed  Google Scholar 

  • Harper JW, Tan M-KM. Ubiquitin pathway proteomics. Mol Cell Proteomics. 2012;11(12):1529–40.

    Google Scholar 

  • He G, Wang H-R, Huang S-K, Huang C-L. Intersectin links WNK kinases to endocytosis of ROMK1. J Clin Invest. 2007;117(4):1078–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heise CJ, Xu B, Deaton SL, Cha S-K, Cheng C-J, Earnest S, et al. Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem. 2010;285(33):25161–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennings JC, Andrini O, Picard N, Paulais M, Huebner AK, Cayuqueo IKL, et al. The ClCK2 chloride channel is critical for salt handling in the distal nephron. J Am Soc Nephrol. 2017;28(1):209–17.

    Article  CAS  PubMed  Google Scholar 

  • Heubl M, Zhang J, Pressey JC, Al Awabdh S, Renner M, Gomez-Castro F, et al. GABA(A) receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl(−)-sensitive WNK1 kinase. Nat Commun. 2017;8(1):1776.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoorn EJ, Walsh SB, McCormick JA, Fürstenberg A, Yang C-L, Roeschel T, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011;17(10):1304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ibeawuchi S-RC, Agbor LN, Quelle FW, Sigmund CD. Hypertension-causing mutations in Cullin3 protein impair RhoA protein ubiquitination and augment the association with substrate adaptors. J Biol Chem. 2015;290(31):19208–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishizawa K, Xu N, Loffing J, Lifton RP, Fujita T, Uchida S, et al. Potassium depletion stimulates Na–Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. Biochem Biophys Res Commun. 2016;480(4):745–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacques T, Picard N, Miller RL, Riemondy KA, Houillier P, Sohet F, et al. Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension. J Am Soc Nephrol. 2013;24(7):1104–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonniya NA, Kar P. Investigating specificity of the anti-hypertensive inhibitor WNK463 against With-No-Lysine kinase family isoforms via multiscale simulations. J Biomol Struct Dyn. 2020;38(5):1306–21.

    Article  CAS  PubMed  Google Scholar 

  • Kadri H, Alamri MA, Navratilova IH, Alderwick LJ, Simpkins NS, Mehellou Y. Towards the development of small-molecule MO25 binders as potential indirect SPAK/OSR1 kinase inhibitors. Chembiochem. 2017;18(5):460–5.

    Article  CAS  PubMed  Google Scholar 

  • Kahle KT, Wilson FH, Leng Q, Lalioti MD, O’Connell AD, Dong K, et al. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet. 2003;35(4):372–6.

    Article  CAS  PubMed  Google Scholar 

  • Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet. 2015;47(11):1282–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(7):1525–36.

    Article  CAS  PubMed  Google Scholar 

  • 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(9):1075–83.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kokubo Y, Kamide K, Inamoto N, Tanaka C, Banno M, Takiuchi S, et al. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. J Hum Genet. 2004;49(9):507–15.

    Article  CAS  PubMed  Google Scholar 

  • Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, et al. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet. 2006;38(10):1124–32.

    Article  CAS  PubMed  Google Scholar 

  • Lazrak A, Liu Z, Huang C-L. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci U S A. 2006;103(5):1615–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MR, Ball SG, Thomas TH, Morgan DB. Hypertension and hyperkalaemia responding to bendrofluazide. Q J Med. 1979;48(190):245–58.

    CAS  PubMed  Google Scholar 

  • Leviel F, Hübner CA, Houillier P, Morla L, El Moghrabi S, Brideau G, et al. The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. J Clin Invest. 2010;120(5):1627–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Hu J, Sun R, Zhao Y, Liu H, Li J, et al. Association between Cullin-3 single-nucleotide polymorphism rs17479770 and essential hypertension in the Male Chinese Han population. Dis Markers [Internet]. 2017 [cited 2017 Jul 31]. Available from: https://www.hindawi.com/journals/dm/2017/3062759/

  • Lin S-H, Yu I-S, Jiang S-T, Lin S-W, Chu P, Chen A, et al. Impaired phosphorylation of Na+–K+–2Cl− cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome. Proc Natl Acad Sci U S A. 2011;108(42):17538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Nussinov R. Flexible cullins in cullin-RING E3 ligases allosterically regulate ubiquitination. J Biol Chem. 2011;286(47):40934–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y-L, Yang S-S, Chen S-J, Lin Y-C, Chu C-C, Huang H-H, et al. OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis. Sci Rep [Internet]. 2016 [cited 2017 Jul 22];6. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112561/

  • Loffing J, Zecevic M, Féraille E, Kaissling B, Asher C, Rossier BC, et al. Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK. Am J Physiol Renal Physiol. 2001;280(4):F675–82.

    Article  CAS  PubMed  Google Scholar 

  • López-Cayuqueo KI, Chavez-Canales M, Pillot A, Houillier P, Jayat M, Baraka-Vidot J, et al. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis. Kidney Int. 2018;94(3):514–23.

    Article  PubMed  Google Scholar 

  • 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(4):456–60, S1–S3

    Article  CAS  PubMed  Google Scholar 

  • Louis-Dit-Picard H, Kouranti I, Rafael C, Loisel-Ferreira I, Chavez-Canales M, Abdel Khalek W, et al. Mutations affecting the conserved acidic WNK1 motif cause inherited hyperkalemic hyperchloremic acidosis. J Clin Invest. 2020;130(12):6379–94.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lytle C, Forbush B. Regulatory phosphorylation of the secretory Na–K–Cl cotransporter: modulation by cytoplasmic Cl. Am J Physiol Cell Physiol. 1996;270(2):C437–48.

    Article  CAS  Google Scholar 

  • Mamenko M, Zaika O, Ilatovskaya DV, Staruschenko A, Pochynyuk O. Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J Biol Chem. 2012;287(1):660–71.

    Article  CAS  PubMed  Google Scholar 

  • Mansfield TA, Simon DB, Farfel Z, Bia M, Tucci JR, Lebe M, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31–42 and 17p11–q21. Nat Genet. 1997;16(2):202–5.

    Article  CAS  PubMed  Google Scholar 

  • Mayan H, Vered I, Mouallem M, Tzadok-Witkon M, Pauzner R, Farfel Z. Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density. J Clin Endocrinol Metab. 2002;87(7):3248–54.

    Article  CAS  PubMed  Google Scholar 

  • McCormick JA, Ellison DH. The WNKs: atypical protein kinases with pleiotropic actions. Physiol Rev. 2011;91(1):177–219.

    Article  CAS  PubMed  Google Scholar 

  • McCormick JA, Mutig K, Nelson JH, Saritas T, Hoorn EJ, Yang C-L, et al. A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metab. 2011;14(3):352–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(11):4723–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mercado CJ, Wang X, Grimm PR, Welling PA, Chang Y-PC. Identification and characterization of alternative STK39 transcripts within human and mouse kidneys reveals species-specific regulation of blood pressure. Physiol Rep. 2020;8(4):e14379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. 2013a;439(1):30–4.

    Article  CAS  PubMed  Google Scholar 

  • 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. 2013b;455(3):339–45.

    Article  CAS  PubMed  Google Scholar 

  • Mulders SM, Knoers NV, Van Lieburg AF, Monnens LA, Leumann E, Wühl E, et al. New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels. J Am Soc Nephrol. 1997;8(2):242–8.

    Article  CAS  PubMed  Google Scholar 

  • Na T, Wu G, Peng J-B. Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions. Biochem Biophys Res Commun. 2012;419(2):293–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Na T, Wu G, Zhang W, Dong W-J, Peng J-B. Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites. Am J Physiol Renal Physiol. 2013;304(1):F8–18.

    Article  CAS  PubMed  Google Scholar 

  • Naito S, Ohta A, Sohara E, Ohta E, Rai T, Sasaki S, et al. Regulation of WNK1 kinase by extracellular potassium. Clin Exp Nephrol. 2011;15(2):195–202.

    Article  CAS  PubMed  Google Scholar 

  • Náray-Fejes-Tóth A, Canessa C, Cleaveland ES, Aldrich G, Fejes-Tóth G. sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial Na+ channels. J Biol Chem. 1999;274(24):16973–8.

    Article  PubMed  Google Scholar 

  • Newhouse S, Farrall M, Wallace C, Hoti M, Burke B, Howard P, et al. Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion. PLoS One [Internet]. 2009 [cited 2017 May 5];4(4). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661139/

  • O’Reilly M, Marshall E, Speirs HJL, Brown RW. 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(10):2447–56.

    Article  PubMed  Google Scholar 

  • 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(1):111–22.

    Article  CAS  PubMed  Google Scholar 

  • Osada Y, Miyauchi R, Goda T, Kasezawa N, Horiike H, Iida M, et al. Variations in the WNK1 gene modulates the effect of dietary intake of sodium and potassium on blood pressure determination. J Hum Genet. 2009;54(8):474–8.

    Article  CAS  PubMed  Google Scholar 

  • 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(39):28755–63.

    Article  CAS  PubMed  Google Scholar 

  • Park HJ, Curry JN, McCormick JA. Regulation of NKCC2 activity by inhibitory SPAK isoforms: KS-SPAK is a more potent inhibitor than SPAK2. Am J Physiol Renal Physiol. 2013;305(12):F1687–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paver WK, Pauline GJ. Hypertension and hyperpotassaemia without renal disease in a young male. Med J Aust. 1964 Aug;22(2):305–6.

    Article  Google Scholar 

  • Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ. Chloride sensing by WNK1 kinase involves inhibition of autophosphorylation. Sci Signal. 2014;7(324):ra41.

    Article  PubMed  PubMed Central  Google Scholar 

  • Picard N, Trompf K, Yang C-L, Miller RL, Carrel M, Loffing-Cueni D, et al. Protein phosphatase 1 inhibitor-1 deficiency reduces phosphorylation of renal NaCl cotransporter and causes arterial hypotension. J Am Soc Nephrol. 2014;25(3):511–22.

    Article  CAS  PubMed  Google Scholar 

  • 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(52):50812–9.

    Article  CAS  PubMed  Google Scholar 

  • Piechotta K, Garbarini N, England R, Delpire E. Characterization of the interaction of the stress kinase SPAK with the Na+–K+–2Cl– cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J Biol Chem. 2003;278(52):52848–56.

    Article  CAS  PubMed  Google Scholar 

  • Pintard L, Willems A, Peter M. Cullin-based ubiquitin ligases: Cul3–BTB complexes join the family. EMBO J. 2004;23(8):1681–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ponce-Coria J, San-Cristobal P, Kahle KT, Vazquez N, Pacheco-Alvarez D, de los Heros P, et al. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proc Natl Acad Sci U S A. 2008;105(24):8458–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pradervand S, Vandewalle A, Bens M, Gautschi I, Loffing J, Hummler E, et al. Dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle syndrome. J Am Soc Nephrol. 2003;14(9):2219–28.

    Article  CAS  PubMed  Google Scholar 

  • Purkerson JM, Schwartz GJ. The role of carbonic anhydrases in renal physiology. Kidney Int. 2007;71(2):103–15.

    Article  CAS  PubMed  Google Scholar 

  • 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(2):63–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson C, Alessi DR. The regulation of salt transport and blood pressure by the WNKSPAK/OSR1 signalling pathway. J Cell Sci. 2008;121(Pt 20):3293–304.

    Article  CAS  PubMed  Google Scholar 

  • Richardson C, Sakamoto K, de los Heros P, Deak M, Campbell DG, Prescott AR, et al. Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. J Cell Sci. 2011;124(Pt 5):789–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ring AM, Leng Q, Rinehart J, Wilson FH, Kahle KT, Hebert SC, et al. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proc Natl Acad Sci U S A. 2007a;104(10):4025–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ring AM, Cheng SX, Leng Q, Kahle KT, Rinehart J, Lalioti MD, et al. WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proc Natl Acad Sci U S A. 2007b;104(10):4020–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodan AR, Jenny A. Chapter 1. WNK kinases in development and disease. In: Jenny A, editor. Current topics in developmental biology [Internet]. Academic Press; 2017. p. 1–47. Available from: http://www.sciencedirect.com/science/article/pii/S0070215316301715

  • 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(9):3433–48.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rozansky DJ, Cornwall T, Subramanya AR, Rogers S, Yang Y-F, David LL, et al. Aldosterone mediates activation of the thiazide-sensitive Na–Cl cotransporter through an SGK1 and WNK4 signaling pathway. J Clin Invest. 2009;119(9):2601–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarikas A, Hartmann T, Pan Z-Q. The cullin protein family. Genome Biol. 2011;12(4):220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saritas T, Borschewski A, McCormick JA, Paliege A, Dathe C, Uchida S, et al. SPAK differentially mediates vasopressin effects on sodium cotransporters. J Am Soc Nephrol. 2013;24(3):407–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 PHAII caused by mutant KLHL3. Mol Cell Biol. 2017;37:e00508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schambelan M, Sebastian A, Rector FC. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption. Kidney Int. 1981;19(5):716–27.

    Article  CAS  PubMed  Google Scholar 

  • Schild L, Canessa CM, Shimkets RA, Gautschi I, Lifton RP, Rossier BC. A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci U S A. 1995;92(12):5699–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scholl UI, Choi M, Liu T, Ramaekers VT, Häusler MG, Grimmer J, et al. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci U S A. 2009;106(14):5842–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultheis PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, et al. Phenotype resembling Gitelman’s syndrome in mice lacking the apical Na+–Cl− cotransporter of the distal convoluted tubule. J Biol Chem. 1998;273(44):29150–5.

    Article  CAS  PubMed  Google Scholar 

  • Schumacher F-R, Sorrell FJ, Alessi DR, Bullock AN, Kurz T. Structural and biochemical characterization of the KLHL3–WNK kinase interaction important in blood pressure regulation. Biochem J. 2014;460(Pt 2):237–46.

    Article  CAS  PubMed  Google Scholar 

  • Schumacher F-R, 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(10):1285–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao L, Ren H, Wang W, Zhang W, Feng X, Li X, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman’s syndrome. Nephron Physiol. 2008;108(3):29–36.

    Article  Google Scholar 

  • Shekarabi M, Girard N, Rivière J-B, Dion P, Houle M, Toulouse A, et al. Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Invest. 2008;118(7):2496–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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 U S A. 2013a;110(19):7838–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata S, Rinehart J, Zhang J, Moeckel G, Castañeda-Bueno M, Stiegler AL, et al. Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia. Cell Metab. 2013b;18(5):660–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata S, Arroyo JP, Castañeda-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 U S A. 2014;111(43):15556–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata K, Sakai H, Huang Q, Kamata H, Chiba Y, Misawa M, et al. Rac1 regulates myosin II phosphorylation through regulation of myosin light chain phosphatase. J Cell Physiol. 2015;230(6):1352–64.

    Article  CAS  PubMed  Google Scholar 

  • 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(2):402–11.

    Article  CAS  PubMed  Google Scholar 

  • 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. 1996a;12(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  • Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, et al. Genetic heterogeneity of Barter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet. 1996b;14(2):152–6.

    Article  CAS  PubMed  Google Scholar 

  • Singer JD, Gurian-West M, Clurman B, Roberts JM. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev. 1999;13(18):2375–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, et al. Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int. 2013;83(5):811–24.

    Article  CAS  PubMed  Google Scholar 

  • Speirs HJL, Morris BJ. WNK4 intron 10 polymorphism is not associated with hypertension. Hypertension. 2004;43(4):766–8.

    Article  CAS  PubMed  Google Scholar 

  • Stehberger PA, Shmukler BE, Stuart-Tilley AK, Peters LL, Alper SL, Wagner CA. Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl−/HCO3− exchanger (slc4a1). J Am Soc Nephrol. 2007;18(5):1408–18.

    Article  CAS  PubMed  Google Scholar 

  • Stokes GS, Gentle JL, Edwards KD, Stewart JH. Syndrome of idiopathic hyperkalaemia and hypertension with decreased plasma renin activity: effects on plasma renin and aldosterone of reducing the serum potassium level. Med J Aust. 1968;2(23):1050–4.

    Article  CAS  PubMed  Google Scholar 

  • Su X-T, Ellison DH, Wang W-H. Kir4.1/Kir5.1 in the DCT plays a role in the regulation of renal K(+) excretion. Am J Physiol Renal Physiol. 2019;316(3):F582–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su X-T, Klett NJ, Sharma A, Allen CN, Wang W-H, Yang C-L, et al. Distal convoluted tubule Cl(−) concentration is modulated via K(+) channels and transporters. Am J Physiol Renal Physiol. 2020;319(3):F534–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(19):5052–60.

    Article  CAS  PubMed  Google Scholar 

  • 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 [Internet]. 2014 [cited 2017 Feb 24];34(3). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212913/

  • Teng-umnuay P, Verlander JW, Yuan W, Tisher CC, Madsen KM. Identification of distinct subpopulations of intercalated cells in the mouse collecting duct. J Am Soc Nephrol. 1996;7(2):260–74.

    Article  CAS  PubMed  Google Scholar 

  • 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(1):39–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1):127–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terris J, Ecelbarger CA, Nielsen S, Knepper MA. Long-term regulation of four renal aquaporins in rats. Am J Physiol. 1996;271(2 Pt 2):F414–22.

    CAS  PubMed  Google Scholar 

  • Thastrup JO, Rafiqi FH, Vitari AC, Pozo-Guisado E, Deak M, Mehellou Y, et al. SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. Biochem J. 2012;441(Pt 1):325–37.

    Article  CAS  PubMed  Google Scholar 

  • Tobin MD, Raleigh SM, Newhouse S, Braund P, Bodycote C, Ogleby J, et al. Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Circulation. 2005;112(22):3423–9.

    Article  CAS  PubMed  Google Scholar 

  • Trepiccione F, Soukaseum C, Baudrie V, Kumai Y, Teulon J, Villoutreix B, et al. Acute genetic ablation of pendrin lowers blood pressure in mice. Nephrol Dial Transplant. 2017;32(7):1137–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 2005;46(4):758–65.

    Article  CAS  PubMed  Google Scholar 

  • Vallon V, Schroth J, Lang F, Kuhl D, Uchida S. Expression and phosphorylation of the Na+–Cl− cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. Am J Physiol Renal Physiol. 2009;297(3):F704–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verissimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene [Internet]. 2001 [cited 2017 Jul 9];20(39). https://doi.org/10.1038/sj.onc.1204726. Available from: https://www.nature.com/onc/journal/v20/n39/full/1204726a.html

  • 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 [Internet]. 2012 [cited 2017 Jul 2];7(5). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365125/

  • 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 LWNK1 specifically in the distal nephron. Proc Natl Acad Sci U S A. 2013;110(35):14366–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villa F, Goebel J, Rafiqi FH, Deak M, Thastrup J, Alessi DR, et al. Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 2007;8(9):839–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(Pt 1):17–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 Renal Physiol. 2015;308(8):F923–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner CA, Finberg KE, Stehberger PA, Lifton RP, Giebisch GH, Aronson PS, et al. Regulation of the expression of the Cl−/anion exchanger pendrin in mouse kidney by acid-base status. Kidney Int. 2002;62(6):2109–17.

    Article  CAS  PubMed  Google Scholar 

  • 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(3):858–68.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, O’Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, et al. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009;106(1):226–31.

    Article  CAS  PubMed  Google Scholar 

  • Warnock DG. Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci. 2001;322(6):302–7.

    Article  CAS  PubMed  Google Scholar 

  • 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(5532):1107–12.

    Article  CAS  PubMed  Google Scholar 

  • Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003;100(2):680–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wimuttisuk W, Singer JD. The Cullin3 ubiquitin ligase functions as a Nedd8-bound heterodimer. Mol Biol Cell. 2007;18(3):899–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G, Peng J-B. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett. 2013;587(12):1717–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu S, Zhu W, Nhan T, Toth JI, Petroski MD, Wolf DA. CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire. Nat Commun. 2013;4:1642.

    Article  PubMed  Google Scholar 

  • Xi B, Chen M, Chandak GR, Shen Y, Yan L, He J, et al. STK39 polymorphism is associated with essential hypertension: a systematic review and meta-analysis. PLoS One [Internet]. 2013 [cited 2017 May 5];8(3). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601080/

  • 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(12):8566–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(22):16795–801.

    Article  CAS  PubMed  Google Scholar 

  • Xu B, Stippec S, Chu P-Y, Lazrak A, Li X-J, Lee B-H, et al. WNK1 activates SGK1 to regulate the epithelial sodium channel. Proc Natl Acad Sci U S A. 2005;102(29):10315–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(11):896–8.

    Article  CAS  PubMed  Google Scholar 

  • Yan Y, Merlin D. Ste20-related proline/alanine-rich kinase: a novel regulator of intestinal inflammation. World J Gastroenterol. 2008;14(40):6115–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang C-L, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na–Cl cotransport. J Clin Invest. 2003;111(7):1039–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 Wnk4(D561A/+) knockin mouse model. Cell Metab. 2007;5(5):331–44.

    Article  CAS  PubMed  Google Scholar 

  • 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(11):1868–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang S-S, Fang Y-W, Tseng M-H, Chu P-Y, Yu I-S, Wu H-C, et al. Phosphorylation regulates NCC stability and transporter activity in vivo. J Am Soc Nephrol. 2013;24(10):1587–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y-S, Xie J, Yang S-S, Lin S-H, Huang C-L. Differential roles of WNK4 in regulation of NCC in vivo. Am J Physiol Renal Physiol. 2018;314(5):F999–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu L, Cai H, Yue Q, Alli AA, Wang D, Al-Khalili O, et al. WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination. Am J Physiol Renal Physiol. 2013;305(1):F31–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1):89–100.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Wang L, Zhang J, Su X-T, Lin D-H, Scholl UI, et al. KCNJ10 determines the expression of the apical Na–Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1). Proc Natl Acad Sci U S A. 2014;111(32):11864–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Siew K, Macartney T, O’Shaughnessy KM, Alessi DR. Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet. 2015;24(16):4545–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Bhuiyan MIH, Zhang T, Karimy JK, Wu Z, Fiesler VM, et al. Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a. Nat Commun. 2020;11(1):78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmerman ES, Schulman BA, Zheng N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr Opin Struct Biol. 2010;20(6):714–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CoRaKID – Inserm UMR_S1155, Paris, France

    Chloé Rafael & Juliette Hadchouel

  2. Sorbonne Université, Faculty of Medicine, Paris, France

    Chloé Rafael & Juliette Hadchouel

Authors
  1. Chloé Rafael
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juliette Hadchouel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juliette Hadchouel .

Editor information

Editors and Affiliations

  1. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy

    Massimiliano Caprio

  2. Université Paris Cité, PARCC, Inserm, Paris, France

    Fabio Luiz Fernandes-Rosa

Rights and permissions

Reprints and permissions

Copyright information

© 2023 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Rafael, C., Hadchouel, J. (2023). Familial Hyperkalemic Hypertension (FHHt). In: Caprio, M., Fernandes-Rosa, F.L. (eds) Hydro Saline Metabolism. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-031-27119-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-27119-9_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-27118-2

  • Online ISBN: 978-3-031-27119-9

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation