Kidney-specific KO of the circadian clock protein PER1 alters renal Na + handling, aldosterone levels, and kidney/adrenal gene expression

• Published in: American journal of physiology. Renal physiology 2022-04, Vol.322 (4), p.F449-F459
• Main Authors: Douma, Lauren G, Costello, Hannah M, Crislip, G Ryan, Cheng, Kit-Yan, Lynch, I Jeanette, Juffre, Alexandria, Barral, Dominique, Masten, Sarah, Roig, Emilio, Beguiristain, Kevin, Li, Wendy, Bratanatawira, Phillip, Wingo, Charles S, Gumz, Michelle L
• Format: Article
• Language: English
• Subjects: Adaptability; Adrenal glands; Aldosterone; Aldosterone - blood; Animals; Blood pressure; Cadherins; Cadherins - metabolism; Circadian Clocks - genetics; Circadian rhythm; Circadian rhythms; CLOCK protein; Collecting duct; Cre recombinase; Diet; Endothelin 1; Endothelins; Excretion; Exons; Gene Expression; Glucocorticoids; Homeostasis; Hypertension; Kidney - metabolism; Kidneys; Male; Mice; Mice, Knockout; Mineralocorticoid receptors; Period 1 protein; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Renal function; Retention; Sodium - metabolism; Sodium Chloride, Dietary - metabolism
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00385.2021

PERIOD 1 (PER1) is a circadian clock transcription factor that is regulated by aldosterone, a hormone that increases blood volume and Na retention to increase blood pressure. Male global knockout (KO) mice develop reduced night/day differences in Na excretion in response to a high-salt diet plus desoxycorticosterone pivalate treatment (HS + DOCP), a model of salt-sensitive hypertension. In addition, global KO mice exhibit higher aldosterone levels on a normal-salt diet. To determine the role of in the kidney, male kidney-specific KO (KS- KO) mice were generated using Ksp-cadherin Cre recombinase to remove exons 2-8 of in the distal nephron and collecting duct. Male KS- KO mice have increased Na retention but have normal diurnal differences in Na excretion in response to HS + DOCP. The increased Na retention is associated with altered expression of glucocorticoid and mineralocorticoid receptors, increased serum aldosterone, and increased medullary endothelin-1 compared with control mice. Adrenal gland gene expression analysis revealed that circadian clock and aldosterone synthesis genes have altered expression in KS- KO mice compared with control mice. These results emphasize the importance of the circadian clock not only in maintaining rhythms of physiological functions but also for adaptability in response to environmental cues, such as HS + DOCP, to maintain overall homeostasis. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis. For the first time, we show that knockout of the circadian clock transcription factor PERIOD 1 using kidney-specific cadherin Cre results in increased renal Na reabsorption, increased aldosterone levels, and changes in gene expression in both the kidney and adrenal gland. Diurnal changes in renal Na excretion were not observed, demonstrating that the clock protein PER1 in the kidney is important for maintaining homeostasis and that this effect may be independent of time of day.