Hypertension Due to Loss of Clock: Novel Insight From the Molecular Analysis of Cry1/Cry2–Deleted Mice

Abstract

In our consumer-oriented society, in which productivity requires around-the-clock activity and demanding shift work, the biologic system that regulates our internal rhythms is being compromised. Poor sleep patterns and hectic lifestyle are detrimental to harmonious physiological and metabolic body systems, with severe impact on public health. Over a trillion peripheral cellular clocks throughout the body, supervised by the master clock located in the hypothalamic suprachiasmatic nucleus, govern most aspects of physiology and behavior. To exemplify the importance of the biologic clock for health, we have recently demonstrated that mice that are arrhythmic because of the deletion of Cry1 and Cry2 clock genes suffer from salt-sensitive hypertension. In these mice, a novel 3β-hydroxyl-steroid dehydrogenase (3β-Hsd) gene under clock control is severely overexpressed specifically in aldosterone-producing cells in the adrenal cortex, leading to hyperaldosteronism and ultimately to salt-sensitive hypertension. The human homologue of this aldosterone-producing, cell-specific enzyme was also characterized and represents a new possibility in the pathogenesis of hypertension.

Development of monoclonal antibodies against the human 3β-hydroxysteroid dehydrogenase/isomerase isozymes

“…In combination with qPCR, these antibodies were used to examine adrenal expression of protein and mRNA for both isozymes. Mice with double deletion of the cryptochrome 1 and 2 developed salt-sensitive hypertension and hyperaldosteronism [5, 6, 12] and a search for steroidogenic enzymes overexpressed in the adrenal showed that the Hsd3b6 was overexpressed in the zona glomerulosa. Of interest the Cyp11b2 enzyme, the last enzyme in the biosynthesis of aldosterone expression was unchanged and the group reached the conclusion that overexpression of the Hsd3b6 resulted in an increased in substrate leading to the increase in aldosterone biosynthesis [5, 6].…”

“…Searching for the cause of the hyperaldosteronism in these mice, the investigators identified increased expression of the Hsd3b6 isozyme only in the zona glomerulosa of the adrenal [5, 6]. The mouse has 6 different genes coding for Hsd3b enzymes, while the human has only two [3].…”

Circadian Clocks and Metabolism

“…Disruption of both Cry1 and Cry2 in mice results in glucose intolerance, elevated corticosterone levels, increased glucocorticoid transactivation in liver, altered lipogenic and steroidogenic pathways, and impaired body growth and liver regeneration (Bur et al 2009; Lamia et al 2011; Matsuo et al 2003; Okamura et al 2011). Knockdown of Cry1 and Cry2 was also found to increase expression of gluconeogenic genes and to augment hepatic glucose production (Zhang et al 2010).…”

Clock genes, pancreatic function, and diabetes

“…Per3 single and Per1/2/3 triple KO mice showed altered body mass regulation when fed a high-fat diet (HFD) [53]. When both Cry1 and Cry2 were deleted, behavioral and molecular circadian rhythms were impaired, lipid metabolism and glucose metabolism were modified, and glucose intolerance emerged [54–56]. Conversely, hepatic Cry1 overexpression in diabetic (db/db) mice led to increased insulin sensitivity and lower blood glucose levels [57].…”