Hypertension Research https://doi.org/10.1038/s41440-018-0148-8 ARTICLE The adrenal gland circadian clock exhibits a distinct phase advance in spontaneously hypertensive rats Sho Tanaka 1 ● Takahiro Ueno 1 ● Akiko Tsunemi 1 ● Chinami Nagura 1 ● Kazunobu Tahira 1 ● Noboru Fukuda 1 ● Masayoshi Soma 1 ● Masanori Abe 1 Received: 22 April 2018 / Accepted: 9 September 2018 © The Japanese Society of Hypertension 2018 Abstract The circadian clock influences a multitude of cellular and biological processes, including blood pressure control. Spontaneously hypertensive rats (SHR) exhibit aberrant circadian rhythms affecting cardiovascular parameters, and they also have abnormal clock gene expression profiles in several organs. Given the important role of the adrenal gland in orchestrating circadian oscillations, we investigated the adrenal gland circadian clock in SHR and control Wistar-Kyoto rats maintained under a 12-hour light–dark cycle. Adrenal glands, livers, and serum samples were collected every 4 h and mRNA was extracted for analysis of clock gene expression. Serum levels of corticosterone and aldosterone were also analyzed. Overall, the circadian profiles of Bmal1, Per2, Per3, Cry1, RevErba, Revervb, and Dbp gene expression in SHR adrenal glands were phase-advanced relative to controls. The expression profile of StAR (a representative gene under circadian control in the adrenal gland), as well as the circadian rhythms of serum concentrations of corticosteroid and aldosterone were also phase advanced. E4bp4 gene expression was significantly higher during the dark period, yet the expression of its transcriptional activator, Rora, was significantly lower throughout the 24 h period in SHR adrenal glands than in controls. This paradoxical high E4bp4 gene expression was, however, not observed in the liver. In addition, Per1, Per2, Per3, Reverba, and Reverbb mRNA tended to be lower in SHR adrenal glands than in controls. Thus, we conclude that SHR possess an abnormal adrenal circadian clock, which may affect the transcriptional regulation of clock-controlled genes, and steroid hormone secretion by the adrenal gland. Key words Adrenal gland ● Circadian clock ● Hypertension ● SHR ● Rats ● Spontaneous hypertensive Introduction A large number of molecular, cellular, and behavioral pro- cesses exhibit circadian (daily) oscillation that is entrained by external Zeitgebers. In mammals, the endogenous oscillator receiving Zeitgeber information resides in the suprachiasmatic nucleus (SCN) of the hypothalamus [1]. One complete cir- cadian oscillation has a period of ~ 24 h, and evolved to permit optimal behavior in response to the daily light cycle [1]. Circadian neural and humoral signals generated by the SCN coordinate rhythmicity in other, peripheral tissues, most of which exhibit robust circadian rhythms at the gene expression and cellular function level. They are considered to be “peripheral clocks”, providing diurnal biological output that is essentially coordinated by SCN-mediated signaling, and thus the external environment [1]. The molecular mechanisms underpinning the circadian clock are transcription–translation feedback loops that together generate a 24 h oscillation in gene and protein expression [2]. In brief, the core feedback loop is centered on the basic helix-loop-helix-PAS transcription factors, circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like protein-1 (BMAL1). CLOCK and BMAL1 heterodimerize and bind E-box elements found in the promoters of their target genes, including Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2), to activate their transcription [1, 2]. The PER and CRY proteins also form a complex together, which ultimately inhibits CLOCK–BMAL1 activity and thus constitutes a negative feedback loop [1, 2]. Chrono, a recently * Sho Tanaka tanakasho13@gmail.com 1 Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Kamicho, Oyaguchi, Itabashi-ku, Tokyo 173- 8610, Japan 1234567890();,: 1234567890();,: