Knockout of the circadian clock protein PER1 results in sex-dependent alterations of ET-1 production in mice in response to a high-salt diet plus mineralocorticoid treatment

Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we...

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Bibliographic Details
Published in:Canadian journal of physiology and pharmacology 2020-09, Vol.98 (9), p.579-586
Main Authors: Douma, Lauren G, Crislip, G Ryan, Cheng, Kit-Yan, Barral, Dominique, Masten, Sarah, Holzworth, Meaghan, Roig, Emilio, Glasford, Krystal, Beguiristain, Kevin, Li, Wendy, Bratanatawira, Phillip, Lynch, I Jeanette, Cain, Brian D, Wingo, Charles S, Gumz, Michelle L
Format: Article
Language:English
Subjects:
Aldosterone
Analysis
Circadian rhythm
Circadian rhythms
CLOCK protein
Collecting duct
Corticosteroids
Diet
Endothelin
Endothelin 1
Endothelin ETA receptors
Endothelin ETB receptors
Gene expression
Genes
Genetic aspects
Genotypes
Hypertension
Period 1 protein
Renal function
RNA
siRNA
Sodium
Wingo, Charles Spurgeon
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Summary:Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we have shown that the endothelin-1 (ET-1) gene is targeted by both PER1 and aldosterone. We hypothesized that ET-1 would exhibit a sex-specific response to HS/DOCP treatment in PER1 KO. Here we show that male, but not female, global PER1 KO mice exhibit a decreased night/day ratio of urinary ET-1. Gene expression analysis revealed significant genotype differences in ET-1 and endothelin A receptor (ET ) expression in male, but not female, mice in response to HS/DOCP. Additionally, both wild-type and global PER1 KO male mice significantly increase endothelin B receptor (ET ) expression in response to HS/DOCP, but female mice do not. Finally, siRNA-mediated knockdown of PER1 in mouse cortical collecting duct cells (mpkCCDc14) resulted in increased ET-1 mRNA expression and peptide secretion in response to aldosterone treatment. These data suggest that PER1 is a negative regulator of ET-1 expression in response to HS/DOCP, revealing a novel mechanism for the regulation of renal Na handling in response to HS/DOCP treatment.
ISSN:0008-4212
1205-7541
DOI:10.1139/cjpp-2019-0688