Otani Tomohiro, Miyake Takahito, Ota Takumi, Yarimizu Daisuke, Nakagawa Yuuki, Murai Iori, Okamura Hitoshi, Hasegawa Emi, Doi Masao
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Division of Physiology and Neurobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Front Endocrinol (Lausanne). 2025 Mar 26;16:1525844. doi: 10.3389/fendo.2025.1525844. eCollection 2025.
The mammalian circadian timing system is organized in a hierarchy, with the master clock residing in the suprachiasmatic nucleus (SCN) of the hypothalamus and subsidiary peripheral clocks in peripheral tissues. Because of the diversity of peripheral tissues and cell-types in the body, the existence of autonomous clock and identification of its potential entrainment signals need to be empirically defined on a cell type-by-cell type basis. In this study, we characterized the basic circadian clock properties of the adrenal zona glomerulosa cells, or ZG cells. Using isolated adrenal explants from mice, dissociated ZG cells from rats, and a related human adrenocortical cell line H295R, we showed that ZG cells possess genetically-encoded, self-sustained and cell-autonomous circadian clock. As to the potential entrainment signals, angiotensin II (Ang II) caused phase-dependent phase-shifts of adrenal ZG cells in cultured slices. Ang II treatment also drove initiation (or reset) of circadian clock gene expression in H295R cells with associated immediate up-regulation of and mRNA expression. We found that the type I Ang II receptor blocker CV11974, one of the most widely used clinical drugs for hypertensive diseases, caused attenuation of the phase resetting of H295R cells. Our data provide a basis to understand and argue for the adrenal gland ZG cells as a component of autonomous and entrainable peripheral clocks.
哺乳动物的昼夜节律计时系统呈层级组织，主时钟位于下丘脑的视交叉上核（SCN），外周组织中存在辅助性外周时钟。由于体内外周组织和细胞类型的多样性，自主时钟的存在及其潜在的同步信号需要在逐个细胞类型的基础上通过实验来确定。在本研究中，我们描述了肾上腺球状带细胞（即ZG细胞）的基本昼夜节律特性。利用从小鼠分离的肾上腺外植体、从大鼠分离的解离ZG细胞以及相关的人肾上腺皮质细胞系H295R，我们表明ZG细胞具有基因编码的、自我维持的和细胞自主的昼夜节律时钟。至于潜在的同步信号，血管紧张素II（Ang II）在培养切片中引起肾上腺ZG细胞的相位依赖性相移。Ang II处理还驱动H295R细胞中昼夜节律时钟基因表达的起始（或重置），并伴随 和 mRNA表达的立即上调。我们发现，I型血管紧张素II受体阻滞剂CV11974（一种最广泛用于治疗高血压疾病的临床药物）会减弱H295R细胞的相位重置。我们的数据为理解和论证肾上腺ZG细胞作为自主且可同步的外周时钟的组成部分提供了依据。
