Circadian expression of H,K-ATPase type 2 contributes to the stability of plasma K⁺ levels

FASEB J. 2012 Jul;26(7):2859-67. doi: 10.1096/fj.11-199711. Epub 2012 Mar 29.


Maintenance by the kidney of stable plasma K(+) values is crucial, as plasma K(+) controls muscle and nerve activity. Since renal K(+) excretion is regulated by the circadian clock, we aimed to identify the ion transporters involved in this process. In control mice, the renal mRNA expression of H,K-ATPase type 2 (HKA2) is 25% higher during rest compared to the activity period. Conversely, under dietary K(+) restriction, HKA2 expression is ∼40% higher during the activity period. This reversal suggests that HKA2 contributes to the circadian regulation of K(+) homeostasis. Compared to their wild-type (WT) littermates, HKA2-null mice fed a normal diet have 2-fold higher K(+) renal excretion during rest. Under K(+) restriction, their urinary K(+) loss is 40% higher during the activity period. This inability to excrete K(+) "on time" is reflected in plasma K(+) values, which vary by 12% between activity and rest periods in HKA2-null mice but remain stable in WT mice. Analysis of the circadian expression of HKA2 regulators suggests that Nrf2, but not progesterone, contributes to its rhythmicity. Therefore, HKA2 acts to maintain the circadian rhythm of urinary K(+) excretion and preserve stable plasma K(+) values throughout the day.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CLOCK Proteins / deficiency
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Gene Expression Regulation, Enzymologic
  • H(+)-K(+)-Exchanging ATPase / classification
  • H(+)-K(+)-Exchanging ATPase / deficiency
  • H(+)-K(+)-Exchanging ATPase / genetics
  • H(+)-K(+)-Exchanging ATPase / metabolism*
  • Homeostasis
  • Kidney / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism
  • Potassium / blood*
  • Potassium / urine
  • Potassium, Dietary / administration & dosage


  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Potassium, Dietary
  • CLOCK Proteins
  • Clock protein, mouse
  • H(+)-K(+)-Exchanging ATPase
  • Potassium