Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6

Area of Science:

• Endocrinology
• Chronobiology
• Cardiovascular Disease

Background:

• Circadian clock malfunction is implicated in various diseases.
• Cryptochrome (Cry1 and Cry2) proteins are essential core components of the circadian clock.
• Hypertension is a significant global health concern.

Purpose of the Study:

• To investigate the link between circadian clock disruption and hypertension.
• To identify the molecular mechanisms underlying salt-sensitive hypertension in mice lacking Cryptochrome.
• To explore the role of Hsd3b6 in circadian clock-regulated aldosterone synthesis.

Main Methods:

• Utilized Cry-null mice lacking Cryptochrome-1 and Cryptochrome-2.
• Assessed aldosterone synthesis and blood pressure in these mice.
• Investigated the expression and activity of type VI 3beta-hydroxyl-steroid dehydrogenase (Hsd3b6).
• Analyzed Hsd3b6 gene and protein levels in adrenal glands.

Main Results:

• Cry-null mice exhibited salt-sensitive hypertension with elevated aldosterone production.
• Hsd3b6 was identified as a novel hypertension risk factor, exclusively expressed in aldosterone-producing cells.
• Hsd3b6 expression and 3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD) activity were constitutively high in Cry-null mice.
• Circadian clock malfunction directly increased Hsd3b6 levels, enhancing aldosterone synthesis.

Conclusions:

• Circadian clock disruption leads to hypertension via increased Hsd3b6 expression and subsequent aldosterone overproduction.
• Hsd3b6 is a critical molecular link between circadian clock malfunction and hypertension development.
• The human HSD3B1 gene may play a similar role, warranting clinical investigation.