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

Abstract

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.

An Integrated View of Potassium Homeostasis

“…64-67 The circadian clock also modulates the activity of genes that regulate potassium homeostasis. 64,68-71 In particular, mice that are deficient in the gene encoding CLOCK have substantial disruption in normal circadian rhythms for renal potassium and sodium excretion and the plasma aldosterone level. 71 Since the CLOCK knockout was global, cell-specific disruption of the protein will be necessary to determine the cell types that sustain the circadian pattern of potassium excretion, sodium excretion, and plasma aldosterone.…”

Regulation of Potassium Homeostasis

“…Gene expression of ROMK is greater during periods of activity, whereas expression of the H 1 -K 1 -ATPase is higher during rest, which correspond to periods when renal K 1 excretion is greater and less, respectively (89). Changes in plasma aldosterone levels may play a contributory role, because circadian rhythm of glucocorticoid synthesis and secretion has been described in the adrenal gland.…”

Physiology and pathophysiology of potassium homeostasis

“…A circadian rhythm exists for gene transcripts that encode proteins involving K ϩ secretion (62). Gene expression of ROMK is greater during periods of activity and daylight, whereas expression of the H ϩ -K ϩ -ATPase is higher during rest and nighttime, corresponding to periods when renal K ϩ excretion is greater and less, respectively (47). There is a pacemaker function regulating K ϩ transport, as indicated by expression of clock genes within cells of the distal nephron.…”