title: Clock genes and salt-sensitive hypertension: a new type of aldosterone-synthesizing enzyme controlled by the circadian clock and angiotensin II.
abstract: With the current societal norm of shiftwork and long working hours, maintaining a stable daily life is becoming very difficult. An irregular lifestyle disrupts circadian rhythms, resulting in the malfunction of body physiology and ultimately leading to lifestyle-related diseases, including hypertension. By analyzing completely arrhythmic Cry1/Cry2 double-knockout (Cry-null) mice, we found salt-sensitive hypertension accompanied by hyperaldosteronism. On the basis of a DNA microarray analysis of the adrenal gland and subsequent biochemical analyses, we discovered that Hsd3b6/HSD3B1, a subtype of 3β-HSD, is markedly overexpressed in aldosterone-producing cells in the Cry-null adrenal cortex. In addition, we found that Hsd3b6/HSD3B1, which converts pregnenolone to progesterone, is a clock-controlled gene and might also be a key enzyme for the regulation of aldosterone biosynthesis, in addition to the previously established CYP11B2, which synthesizes aldosterone from deoxycorticosterone. Importantly, angiotensin II induces HSD3B1 via the transcription factor NGFIB in human adrenocortical H295R cells, similarly to CYP11B2. As HSD3B1 levels are abnormally high in the adrenal aldosterone-producing cells of idiopathic hyperaldosteronism (IHA), the temporal component of this system in the pathophysiology of IHA is a promising area for future research.
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Doi
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kojima
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D017673:Sodium Chloride, Dietary
chemical_list: D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D000450:Aldosterone; D015096:3-Hydroxysteroid Dehydrogenases; D056926:CLOCK Proteins