Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

The kidneys regulate many vital functions that require precise control throughout the day. These functions, such as maintaining sodium balance or regulating arterial pressure, rely on an intrinsic clock mechanism that was commonly believed to be controlled by the central nervous system. Mounting evidence in recent years has unveiled previously underappreciated depth of influence by circadian rhythms and clock genes on renal function, at the molecular and physiological level, independent of other external factors. The impact of circadian rhythms in the kidney also affects individuals from a clinical standpoint, as the loss of rhythmic activity or clock gene expression have been documented in various cardiovascular diseases. Fortunately, the prognostic value of examining circadian rhythms may prove useful in determining the progression of a kidney-related disease, and chronotherapy is a clinical intervention that requires consideration of circadian and diurnal rhythms in the kidney. In this review, we discuss evidence of circadian regulation in the kidney from basic and clinical research in order to provide a foundation on which a great deal of future research is needed to expand our understanding of circadian relevant biology.

ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ET _A and ET _B receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.

Male spontaneously hypertensive rats (SHR) have higher blood pressure, blunted pressure–natriuresis relationship, and accelerated progression of renal injury compared with female SHR. Renal medullary prostanoids mediate vascular tone, salt and water balance, and renin release and, as a result, are involved in the maintenance of renal blood flow and the pathogenesis of hypertension. The aim of this study was to determine whether a gender difference exists in prostanoid production in SHR and whether sex steroids influence prostaglandin (PG) production. Thirteen-week-old intact and gonadectomized male and female SHR rats were placed in metabolic cages for 24-hour urine collection. Prostanoid excretion was determined using enzyme immunoassay. Kidneys were isolated and separated into outer and inner medulla for Western blot analysis. Female SHR had enhanced urinary excretion of PG E ₂ (PGE ₂ ) metabolites and thromboxane B ₂ , an indicator of renal thromboxane production, compared with male SHR. There were no gender differences in excretion of systemic thromboxane or prostacyclin. Correspondingly, female SHR had enhanced microsomal PGE ₂ synthase protein expression in the renal inner medulla and greater cyclooxygenase-2 (COX-2) expression in the outer medulla. Orchidectomy was associated with increased PGE ₂ metabolite excretion and microsomal PGE synthase protein expression. Thromboxane B ₂ excretion was not affected by gonadectomy in either male or female SHR. Protein expressions of COX and cytoplasmic PGE ₂ synthase in the renal medulla were unchanged by gonadectomy in both sexes. These results demonstrate a sexual dimorphism in renal production of prostanoids in SHR and that PGE production is testosterone sensitive and estrogen insensitive.

Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; P < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on; P > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion.

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 (ET_B) receptors. Furthermore, ET_Breceptor-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 ET_Breceptor 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). ET_Breceptor 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 ET_Bblockade (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.