Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6.
Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3beta-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development of hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6.
Doi
Masao
M
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Takahashi
Yukari
Y
Komatsu
Rie
R
Yamazaki
Fumiyoshi
F
Yamada
Hiroyuki
H
Haraguchi
Shogo
S
Emoto
Noriaki
N
Okuno
Yasushi
Y
Tsujimoto
Gozoh
G
Kanematsu
Akihiro
A
Ogawa
Osamu
O
Todo
Takeshi
T
Tsutsui
Kazuyoshi
K
van der Horst
Gijsbertus T J
GT
Okamura
Hitoshi
H
D000450:Aldosterone / Q000096:biosynthesis / Q000097:blood; D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D011375:Progesterone Reductase / Q000235:genetics / Q000502:physiology*; D013251:Steroid Isomerases / Q000235:genetics / Q000502:physiology*; D015384:Zona Glomerulosa / Q000201:enzymology*
C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D007527:Isoenzymes; D000450:Aldosterone; D011375:Progesterone Reductase; D013251:Steroid Isomerases; C022660:steroid delta-isomerase