scholarly journals Female C57BL/6J mice lacking the circadian clock protein PER1 are protected from nondipping hypertension

2019 ◽  
Vol 316 (1) ◽  
pp. R50-R58 ◽  
Author(s):  
Lauren G. Douma ◽  
Kristen Solocinski ◽  
Meaghan R. Holzworth ◽  
G. Ryan Crislip ◽  
Sarah H. Masten ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Dependent Manner ◽  
High Salt Diet ◽  
Female Mice ◽  
Night And Day ◽  
Long Acting ◽  
First Time ◽  
Cardiovascular Rhythms ◽  
Clock Protein

The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs, including blood pressure. Our laboratory has previously demonstrated the importance of the clock protein period 1 (PER1) in blood pressure regulation in male mice. Briefly, a high-salt diet (HS; 4% NaCl) plus injection with the long-acting mineralocorticoid deoxycorticosterone pivalate (DOCP) resulted in nondipping hypertension [<10% difference between night and day blood pressure (BP) in Per1-knockout (KO) mice but not in wild-type (WT) mice]. To date, there have been no studies that have examined the effect of a core circadian gene KO on BP rhythms in female mice. The goal of the present study was to determine whether female Per1-KO mice develop nondipping hypertension in response to HS/DOCP treatment. For the first time, we demonstrate that loss of the circadian clock protein PER1 in female mice does not significantly change mean arterial pressure (MAP) or the BP rhythm relative to female C57BL/6 WT control mice. Both WT and Per1-KO female mice experienced a significant increase in MAP in response to HS/DOCP. Importantly, however, both genotypes maintained a >10% dip in BP on HS/DOCP. This effect is distinct from the nondipping hypertension seen in male Per1-KO mice, demonstrating that the female sex appears to be protective against PER1-mediated nondipping hypertension in response to HS/DOCP. Together, these data suggest that PER1 acts in a sex-dependent manner in the regulation of cardiovascular rhythms.

scholarly journals Loss of circadian gene Bmal1 in the collecting duct lowers blood pressure in male, but not female, mice

2020 ◽  
Vol 318 (3) ◽  
pp. F710-F719 ◽  
Author(s):  
Dingguo Zhang ◽  
Chunhua Jin ◽  
Ijeoma E. Obi ◽  
Megan K. Rhoads ◽  
Reham H. Soliman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
High Salt ◽  
Dependent Manner ◽  
Type B ◽  
Circadian Gene ◽  
High Salt Diet ◽  
Salt Diet ◽  
Female Mice ◽  
Renal Inner Medulla

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.

Changes of Blood Pressure Rhythm and Clock Protein Expression Levels in Spontaneously Hypertensive Rats After Ischemia-Reperfusion

2021 ◽  
Author(s):  
Jing Jin ◽  
Yumeng Liu ◽  
Jing Huang ◽  
Dong Zhang ◽  
Jian Ge ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Protein Expression ◽  
Circadian Clock ◽  
Spontaneously Hypertensive Rats ◽  
Ischemia Reperfusion ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Expression Levels ◽  
The Relationship ◽  
Clock Protein

Abstract Objective A variety of circadian patterns of blood pressure after ischemic stroke in patients with essential hypertension appear to be a potential risk of stroke recurrence, but the mechanism is still unclear. This study intends to reveal the changes in blood pressure rhythm and circadian clock protein expression levels in spontaneously hypertensive rats (SHR) after ischemia-reperfusion, and the relationship between the two. Methods Using the SHR middle cerebral artery occlusion experimental model, the systolic blood pressure was continuously monitored for 24 hours after the operation to observe the blood pressure rhythm. The rat tail vein blood was taken every 3h, and the serum CLOCK, BMAL1, PER1 and CRY1 protein expression levels were detected by Elisa. Pearson correlation analysis counted the relationship between SHR blood pressure rhythm and circadian clock protein fluctuation after ischemia-reperfusion. Results The proportion of abnormal blood pressure patterns in the SHR + tMCAO group was significantly higher than that in the SHR group, the serum CLOCK expression was relatively constant, and the circadian rhythm of BMAL1, PER1 and CRY1 protein expression changed significantly. Pearson analysis showed that PER1 protein level was negatively correlated with dipper (r = -0.565, P = 0.002) and extreme-dipper (r = -0.531, P = 0.001) blood pressure, and was significantly positively correlated with non-dipper blood pressure (r = 0.620, P < 0.001). Conclusion The rhythm pattern of blood pressure after ischemia-reperfusion in SHR is obviously disordered, and it is closely related to the regulation of Per1 gene.

Abstract 096: Leptin and High Salt Diet Induce Greater Increases in Blood Pressure in Female than Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Eric J Belin de Chantemele
Keyword(s):  
Blood Pressure ◽  
Recovery Period ◽  
Pressure Rise ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
Blood Pressure Responses

Recent studies by our group demonstrated that leptin is a direct regulator of aldosterone secretion and increases blood pressure via sex-specific mechanisms involving leptin-mediated activation of the aldosterone-mineralocorticoid receptor signaling pathway in females and sympatho-activation in males. Although it is well accepted that females secrete more leptin and aldosterone than males, it is unknown whether leptin infusion raises blood pressure similarly in male and female mice and whether higher aldosterone levels sensitize females to salt-induced hypertension. We hypothesized that female mice would be more sensitive to leptin than males and also have a potentiated blood pressure rise in response to high salt diet compared to males. Male and female Balb/C mice were implanted with radiotelemeters for continuous measurement of mean arterial pressure (MAP) at 10 weeks of age. MAP was measured for seven days prior to feeding with a high-salt diet (HS, 4%NaCl) for seven days. Following a recovery period, animals were then implanted with osmotic minipumps containing leptin (0.9mg/kg/day) recorded for seven days. Baseline MAP was similar between males and females (101.3±2.9 vs 99.3±3.7 mmHg, n=4 and 5, respectively), however, HS diet resulted in a greater MAP increase in females (15.0±2.6 mmHg) compared to males (3.1±4.5 mmHg, P<0.05). MAP with leptin treatment was increased with leptin in females moreso than in males, however, this did not reach significance (6.8±5.8 vs 1.8±5.9 mmHg, respectively). This potential sex difference in blood pressure responses to leptin was not associated with changes in body weight (0.07±0.44 vs -0.22±0.2 g, respectively) nor changes in blood glucose (-19.67±15.06 vs -15.4±11.4 mg/dl, respectively) in males and females in response to leptin. In summary, female mice are more sensitive to HS diet-induced blood pressure increases than males. Females may be more sensitive to leptin-mediated blood pressure increases than males. Further investigation is needed to determine whether these sex differences in blood pressure responses to HS diet and leptin are mediated by aldosterone or other mechanisms.

Abstract 130: Modulation of Salt and Mineralocorticoid Sensitivity of Blood Pressure by the Circadian Clock Protein Per1

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kristen Solocinski ◽  
Xuerong Wen ◽  
Kit-Yan Cheng ◽  
Jeanette Lynch ◽  
Brian D Cain ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Clock Gene ◽  
Salt Intake ◽  
Disease Risk ◽  
Male Mice ◽  
Night Time ◽  
Increased Risk ◽  
Time Map ◽  
Clock Protein

The circadian clock is important for maintaining rhythms in physiological functions including blood pressure (BP). Circadian disruption leads to increased disease risk. The clock has also been implicated in the maintenance of a normal dip in BP at night. In humans, non-dipping (night/day difference in BP<10%) is associated with an increased risk of cardiovascular and kidney disease. Dipping status can also be affected by salt intake and by hormones such as the mineralocorticoid aldosterone. The goal of this study was to determine the effects of a high salt (HS, 4% NaCl) diet plus mineralocorticoid (deoxycorticosterone pivalate (DOCP)) on BP regulation by the circadian clock protein Per1 in C57BL/6J mice. BP was monitored in conscious, unrestrained male mice by radiotelemetry and values are reported as mean arterial pressure (MAP) ± SEM. Under control conditions, MAP in male WT mice was 112.5 ± 1.08 mmHg during the night when mice are active and decreased to 102.1 ± 1.7 mmHg during the day, a “dip” in MAP of 9.2 ± 1.3%. Similarly, Per1 KO mice dip 14 ± 1.4%, with night time MAP of 119.8 ± .9 mmHg which decreased to 103 ± 1.4 mmHg during the day. On HS/DOCP, WT mice MAP decreased from 114.5 ± 1.1 mmHg to 101.5 ± 1.92 mmHg (night indicated by shaded bars in figure). This 11.4 ± 1.9% dip in WT mice was not significantly different from what was observed under control conditions. In contrast, Per1 KO mice display a significantly attenuated dip of 5.7 ± 1.4% with night time MAP of 125.3 ± 1.5 mmHg dropping to 118.1 ± 1 mmHg during the inactive day period (p<0.05). Thus, HS/DOCP treatment in Per1 KO mice leads to non-dipping hypertension. This is the first report of this phenotype in a single clock gene KO.

scholarly journals Sex dependent compensatory mechanisms to preserve blood pressure homeostasis in PGI2 receptor deficient mice

2020 ◽  
Author(s):  
Soon Yew Tang ◽  
Seán T. Anderson ◽  
Hu Meng ◽  
Dimitra Sarantopoulou ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Oxidant Stress ◽  
High Salt ◽  
Prostaglandin E ◽  
High Salt Diet ◽  
Salt Loading ◽  
Salt Diet ◽  
Female Mice ◽  
The Impact ◽  
Deficient Mice

AbstractInhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown.To address how differential effects on PGE2 and PGI2 might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr KOs). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr KO mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 KO mice. Suppression of PGE2 biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr KO mice and in Ipr /Ldlr DKOs. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.

Abstract 10: Mouse Recombinant Soluble PRR-induced Increase Of Blood Pressure Is Sex-dependant In High Fat-fed Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Audrey A Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Wen Su ◽  
Ming C Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
The Body ◽  
Soluble Form ◽  
Dependent Manner ◽  
High Fat ◽  
Female Mice ◽  
Prorenin Receptor ◽  
Atropine Treatment ◽  
Fat Feeding

Obesity is a major risk factor for hypertension. Although the renin-angiotensin system (RAS) contributes to the sex difference of blood pressure (BP) control, whether the prorenin receptor (PRR) and its soluble form (sPRR) play a role in the sexual dimorphism of BP is not clear. We previously demonstrated that, in high fat (HF)-fed male C57BL/6 mice, the infusion of mouse recombinant sPRR increased systolic blood pressure (SBP) by the sympatho-excitatory effects of leptin on BP. Therefore, in the present study, we aim to address whether mouse recombinant sPRR influences the BP in HF-fed female mice. To test this hypothesis, C57BL/6 female mice were fed a HF diet for 32 weeks and were implanted with radiotelemetry transmitter. After 24 weeks of high fat feeding, female mice (5-6/group) were implanted with osmotic pumps and infused with either saline (veh) or sPRR for 3 to 4 weeks. In contrast to male mice, the infusion of sPRR (30 μg/kg/day) did not change significantly the SBP (24hSBP; veh: 135 ± 7; sPRR: 134 ± 4 mmHg; P>0.05) and the baroreflex sensitivity. The decrease in BP mediated by chlorisondamine treatment was not significantly different between female mice infused with vehicle or sPRR (ΔSBP; veh: -11 ± 9; sPRR: -16 ± 7 mmHg; P>0.05). In addition, sPRR infusion did not affect the bradycardic or tachycardic responses after propranolol or atropine treatment respectively. Moreover, the decrease of SBP induced by losartan was similar in mice infused with vehicle or sPRR (ΔSBP; veh: -9 ± 4; sPRR: -10 ± 3 mmHg; P>0.05). Similar results were obtained using higher dose of sPRR (60 μg/kg/day). In female mice, sPRR infusion did not increase significantly the body weight (veh: 32.7 ± 2.5 g; sPRR: 35.8 ± 4.2 g; P>0.05), the white adipose tissue weight (WAT; veh: 3.0 ± 0.7g; sPRR: 3.7 ± 1.6 g; P>0.05) or circulating leptin levels (veh: 12.0 ± 7.6 ng/ml; sPRR: 15.5 ± 9.5 ng/ml; P>0.05). In conclusion, in contrast to male, female mice are protected from sPRR-induced increase in BP. sPRR did not increase circulating leptin suggesting that sPRR-induced leptin increase is regulated in a sex-dependent manner. Other pathways could participate to the protection against sPRR-induced increase in BP in female mice such as the vasodilator arm of the RAS and/or the hormonal status of the female mice.

Abstract P216: The Circadian Clock Protein BMAL1 in the Kidney Contributes to Blood Pressure Control in Male Mice

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Gene R Crislip ◽  
Lauren G Douma ◽  
Sarah Masten ◽  
Kit-Yan Cheng ◽  
I. J Lynch ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Blood Pressure Control ◽  
Pressure Control ◽  
Male Mice ◽  
Clock Protein

scholarly journals Inhibition of αENaC expression and ENaC activity following blockade of the circadian clock-regulatory kinases CK1δ/ε

2012 ◽  
Vol 303 (7) ◽  
pp. F918-F927 ◽  
Author(s):  
Jacob Richards ◽  
Megan M. Greenlee ◽  
Lauren A. Jeffers ◽  
Kit-Yan Cheng ◽  
Laijing Guo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Single Channel ◽  
Collecting Duct ◽  
Transcriptional Response ◽  
Mrna Levels ◽  
Cortical Collecting Duct ◽  
Nuclear Entry ◽  
Protein Levels ◽  
Clock Protein

Increasing evidence suggests that the circadian clock plays an important role in the control of renal function and blood pressure. We previously showed that the circadian clock protein Period (Per)1, positively regulates the expression of the rate limiting subunit of the renal epithelial sodium channel (αENaC), which contributes to blood pressure regulation. Casein kinases 1δ and 1ε (CK1δ/ε) are critical regulators of clock proteins. CK1δ/ε must phosphorylate the circadian clock protein Per1 in order for the latter to enter the nucleus. We used a commercially available CK1δ/ε inhibitor, PF670462, to test the effect of CK1δ/ε blockade and inhibited Per1 nuclear entry on αENaC in a model of the renal cortical collecting duct (mpkCCDc14 cells). CK1δ/ε blockade prevented Per1 and Clock from interacting with an E-box from the αENaC promoter. CK1δ/ε inhibition reduced αENaC mRNA levels by <60%. A similar decrease in αENaC mRNA was observed following siRNA-mediated CK1δ/ε knock-down. Inhibition of CK1δ/ε effectively prevented the transcriptional response of αENaC to aldosterone, suggesting an interaction between the circadian clock and aldosterone-mediated regulation of αENaC. CK1δ/ε inhibition significantly reduced αENaC but increased Caveolin-1 membrane protein levels; transepithelial current, a measure of ENaC activity, was decreased. Importantly, single channel analysis in amphibian renal cells demonstrated a dramatic decrease in the number of patches with observable ENaC current following CK1δ/ε inhibition. The present study shows for the first time that CK1δ/ε inhibition and impaired Per1 nuclear entry results in decreased αENaC expression and ENaC activity, providing further support for direct control of ENaC by the circadian clock.

scholarly journals 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

2020 ◽  
Vol 98 (9) ◽  
pp. 579-586 ◽  
Author(s):  
Lauren G. Douma ◽  
G. Ryan Crislip ◽  
Kit-Yan Cheng ◽  
Dominique Barral ◽  
Sarah Masten ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Collecting Duct ◽  
High Salt ◽  
Negative Regulator ◽  
Specific Response ◽  
Cortical Collecting Duct ◽  
High Salt Diet ◽  
Salt Diet ◽  
Female Mice ◽  
Endothelin B

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 (ETA) 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 (ETB) 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.

scholarly journals Evidence for a Putative Circadian Kiss-Clock in the Hypothalamic AVPV in Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (8) ◽  
pp. 2999-3011 ◽  
Author(s):  
David Chassard ◽  
Isabelle Bur ◽  
Vincent-Joseph Poirel ◽  
Jorge Mendoza ◽  
Valérie Simonneaux
Keyword(s):  
Circadian Clock ◽  
Time Of Day ◽  
Daily Rhythm ◽  
Circadian Period ◽  
Suprachiasmatic Nuclei ◽  
Intact Female ◽  
Lh Surge ◽  
Female Mice ◽  
Periventricular Nucleus ◽  
Clock Protein

Abstract The kisspeptin (Kp) neurons in the anteroventral periventricular nucleus (AVPV) are essential for the preovulatory LH surge, which is gated by circulating estradiol (E2) and the time of day. We investigated whether AVPV Kp neurons in intact female mice may be the site in which both E2 and daily signals are integrated and whether these neurons may host a circadian oscillator involved in the timed LH surge. In the afternoon of proestrous day, Kp immunoreactivity displayed a marked and transient decrease 2 hours before the LH surge. In contrast, Kp content was stable throughout the day of diestrus, when LH levels are constantly low. AVPV Kp neurons expressed the clock protein period 1 (PER1) with a daily rhythm that is phase delayed compared with the PER1 rhythm measured in the main clock of the suprachiasmatic nuclei (SCN). PER1 rhythm in the AVPV, but not in the SCN, exhibited a significant phase delay of 2.8 hours in diestrus as compared with proestrus. Isolated Kp-expressing AVPV explants from PER2::LUCIFERASE mice displayed sustained circadian oscillations of bioluminescence with a circadian period (23.2 h) significantly shorter than that of SCN explants (24.5 h). Furthermore, in AVPV explants incubated with E2 (10 nM to 1 μM), the circadian period was lengthened by 1 hour, whereas the SCN clock remained unaltered. In conclusion, these findings indicate that AVPV Kp neurons display an E2-dependent daily rhythm, which may possibly be driven by an intrinsic circadian clock acting in combination with the SCN timing signal.

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