Background The novel estrogen receptor, G‐protein–coupled estrogen receptor ( GPER ), is responsible for rapid estrogen signaling. GPER activation elicits cardiovascular and nephroprotective effects against salt‐induced complications, yet there is no direct evidence for GPER control of renal Na + handling. We hypothesized that GPER activation in the renal medulla facilitates Na + excretion. Methods and Results Herein, we show that infusion of the GPER agonist, G1, to the renal medulla increased Na + excretion in female Sprague Dawley rats, but not male rats. We found that GPER mRNA expression and protein abundance were markedly higher in outer medullary tissues from females relative to males. Blockade of GPER in the renal medulla attenuated Na + excretion in females. Given that medullary endothelin 1 is a well‐established natriuretic factor that is regulated by sex and sex steroids, we hypothesized that GPER activation promotes natriuresis via an endothelin 1–dependent pathway. To test this mechanism, we determined the effect of medullary infusion of G1 after blockade of endothelin receptors. Dual endothelin receptor subtype A and endothelin receptor subtype B antagonism attenuated G1‐induced natriuresis in females. Unlike males, female mice with genetic deletion of GPER had reduced endothelin 1, endothelin receptor subtype A, and endothelin receptor subtype B mRNA expression compared with wild‐type controls. More important, we found that systemic GPER activation ameliorates the increase in mean arterial pressure induced by ovariectomy. Conclusions Our data uncover a novel role for renal medullary GPER in promoting Na + excretion via an endothelin 1–dependent pathway in female rats, but not in males. These results highlight GPER as a potential therapeutic target for salt‐sensitive hypertension in postmenopausal women.
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.
The diurnal rhythms of sodium handling and blood pressure are thought to be regulated by clock genes, such as Bmal1. However, little is known about the regulation of these factors by Bmal1, especially in rats. Using a novel whole-body Bmal1 knockout rat model ( Bmal1 − /− ), we hypothesized that time of day regulation of sodium excretion is dependent on Bmal1. Using telemetry to continuously record mean arterial pressure, we observed that male and female Bmal1 −/− rats had significantly reduced mean arterial pressure over the course of 24 hours compared with littermate controls. The circadian mean arterial pressure pattern remained intact in both sexes of Bmal1 −/− rats, which is in contrast to the Bmal1 −/− mouse model. Male Bmal1 −/− rats had no significant difference in baseline sodium excretion between 12-hour active and inactive periods, indicating a lack of diurnal control independent of maintained mean arterial pressure rhythms. Female Bmal1 −/− rats, however, had significantly greater sodium excretion during the active versus inactive period similar to controls. Thus, we observed a clear dissociation between circadian blood pressure and control of sodium excretion that is sex dependent. These findings are consistent with a more robust ability of females to maintain control of sodium excretion, and furthermore, demonstrate a novel role for Bmal1 in control of diurnal blood pressure independent of sodium excretion.
Cardiovascular and renal physiology follow strong circadian rhythms. For instance, renal excretion of solutes and water is higher during the active period compared to the inactive period, and blood pressure peaks early in the beginning of the active period of both diurnal and nocturnal animals. The control of these rhythms is largely dependent on the expression of clock genes both in the central nervous system and within peripheral organs themselves. Although it is understood that the central and peripheral clocks interact and communicate, few studies have explored the specific mechanism by which various organ systems within the body are coordinated to control physiological processes. The renal sympathetic nervous innervation has long been known to have profound effects on renal function, and because the sympathetic nervous system follows strong circadian rhythms, it is likely that autonomic control of the kidney plays an integral role in modulating renal circadian function. This review highlights studies that provide insight into this interaction, discusses areas lacking clarity, and suggests the potential for future work to explore the role of renal autonomics in areas such as blood pressure control and chronic kidney disease.
The attention for the control of dietary risk factors involved in the development of hypertension, includes a large effort on dietary salt restrictions. Ample studies show the beneficial role of limiting dietary sodium as a lifestyle modification in the prevention and management of essential hypertension. Not until the past decade or so have studies more specifically investigated diurnal variations in renal electrolyte excretion, which led us to the hypothesis that timing of salt intake may impact cardiovascular health and blood pressure regulation. Cell autonomous molecular clocks as the name implies, function independently to maintain optimum functional rhythmicity in the face of environmental stressors such that cellular homeostasis is maintained at all times. Our understanding of mechanisms influencing diurnal patterns of sodium excretion and blood pressure has expanded with the discovery of the circadian clock genes. In this review, we discuss what is known about circadian regulation of renal sodium handling machinery and its influence on blood pressure regulation, with timing of sodium intake as a potential modulator of the kidney clock.
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