Loss of circadian geneBmal1in the collecting duct lowers blood pressure in male, but not female, mice

Abstract

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETB receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETB blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.

Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure

“… 45 , 46 Our laboratory recently showed that Bmal1 in the kidney collecting duct does not contribute to BP rhythm regulation, nor the kidney excretory rhythm. 16 Crislip et al recently reported that loss of Bmal1 in the entire distal nephron also did not alter the rhythm of BP when on an ad libitum diet. 43 Work from Firsov and colleagues has also shown that Bmal1 in different parts of the kidney (renal tubular cells, renin-secreting cells, and podocytes) also does not appear to directly regulate the circadian pattern of BP.…”

“…This was largely due to a drop in BP when the animals were fasting consistent with a lower overall BP noted in other clock gene knockout animals including the Bmal1 KO rat. 13 , 16 , 43 , 44 These results suggest that follow-up studies will be needed to more specifically determine how the loss of Bmal1 causes the observed changes in eating behavior and the BP phenotype. Many of the other clock gene-specific KO mice have abnormal BP rhythms and so we will also need to determine the extent to which feeding behavior is driving those phenotypes, if any.…”

“…Telemetry transmitters (TA11-PAC10, Data Science International, St. Paul, MN) were implanted into the right carotid artery of mice as previously described to measure BP, heart rate (HR), and activity. 16 Mice were allowed to recover from surgery at least 10 days prior to starting any experiment. Telemetry data were recorded at 2000 samples/s in 3-min bins every 20 min.…”

“… 10 – 11 Of note, global genetic deletion of Bmal1 in mice resulted in the loss of a diurnal BP rhythm along with many other circadian phenotypes. 13 Many tissue-specific Bmal1 knockout mouse models have also been generated to determine the mechanism for the arrhythmic BP phenotype observed in global Bmal1 knockout mice 14 – 16 ; however, the complete abolishment of BP rhythm was not seen in any of the tissue/cell-specific models. For example, Gong et al showed that loss of Bmal1 in smooth muscle cells significantly reduced, but did not eliminate, the day–night difference of BP.…”

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

“…10,11 Recently, several studies demonstrated that Bmal1 plays critical roles in the maintenance of blood pressure homeostasis and the rhythmic regulation of renal physiological function. [12][13][14] A combined transcriptomic and metabolomic analysis revealed that Bmal1 in renal tubular cells is involved in the renal metabolic and homeostatic processes as well as drug disposition, while is not a prerequisite for controlling GFR or water and electrolyte balance. 15 In contrast, when Bmal1 was deficient in the renin-secreting granular cells of the juxtaglomerular apparatus, the circadian patterns of urinary electrolyte excretion, as well as the GFR and plasma renin and aldosterone levels, were all significantly modified, which was accompanied by a reduction of baseline blood pressure.…”