Role of WNK4 and kidney-specific WNK1 in mediating the effect of high dietary K+ intake on ROMK channel in the distal convoluted tubule

Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F223-F230. doi: 10.1152/ajprenal.00050.2018. Epub 2018 Apr 18.


With-no-lysine kinase 4 (WNK4) and kidney-specific (KS)-WNK1 regulate ROMK (Kir1.1) channels in a variety of cell models. We now explore the role of WNK4 and KS-WNK1 in regulating ROMK in the native distal convoluted tubule (DCT)/connecting tubule (CNT) by measuring tertiapin-Q (TPNQ; ROMK inhibitor)-sensitive K+ currents with whole cell recording. TPNQ-sensitive K+ currents in DCT2/CNT of KS- WNK1-/- and WNK4-/- mice were significantly smaller than that of WT mice. In contrast, the basolateral K+ channels (a Kir4.1/5.1 heterotetramer) in the DCT were not inhibited. Moreover, WNK4-/- mice were hypokalemic, while KS- WNK1-/- mice had normal plasma K+ levels. High K+ (HK) intake significantly increased TPNQ-sensitive K+ currents in DCT2/CNT of WT and WNK4-/- mice but not in KS- WNK1-/- mice. However, TPNQ-sensitive K+ currents in the cortical collecting duct (CCD) were normal not only under control conditions but also significantly increased in response to HK in KS- WNK1-/- mice. This suggests that the deletion of KS-WNK1-induced inhibition of ROMK occurs only in the DCT2/CNT. Renal clearance study further demonstrated that the deletion of KS-WNK1 did not affect the renal ability of K+ excretion under control conditions and during increasing K+ intake. Also, HK intake did not cause hyperkalemia in KS- WNK1-/- mice. We conclude that KS-WNK1 but not WNK4 is required for HK intake-induced stimulation of ROMK activity in DCT2/CNT. However, KS-WNK1 is not essential for HK-induced stimulation of ROMK in the CCD, and the lack of KS-WNK1 does not affect net renal K+ excretion.

Keywords: K+ excretion; Kir1.1; Kir4.1; hyperkalemia; hypokalemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Female
  • Genotype
  • Hyperkalemia / enzymology
  • Hyperkalemia / genetics
  • Hypokalemia / enzymology
  • Hypokalemia / genetics
  • In Vitro Techniques
  • Kidney Tubules, Distal / enzymology*
  • Male
  • Membrane Potentials
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Potassium, Dietary / metabolism*
  • Potassium, Dietary / urine
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Renal Elimination
  • WNK Lysine-Deficient Protein Kinase 1 / deficiency
  • WNK Lysine-Deficient Protein Kinase 1 / genetics
  • WNK Lysine-Deficient Protein Kinase 1 / metabolism*


  • Kcnj1 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Potassium, Dietary
  • Prkwnk4 protein, mouse
  • Protein Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse