ROLE OF CRYPTOCHROME-1 AND CRYPTOCHROME-2 IN ALDOSTERONE SECRETION

Abstract

Objective: Knock-out mice for the genes Cry1 and Cry2 lack the circadian clock components Cryptochrome-1 and Cryptochrome-2 and display a form of hyperaldosteronism sustained by the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6). Type I 3β-hydroxyl-steroid dehydrogenase (HSD3B1) gene is the human counterpart of the murine Hsd3b6. The aim of this study was to evaluate the role of CRY1 and CRY2 and their potential interaction with HSD3B isoforms in human adrenocortical physiopathology. Design and method: The study included 46 sporadic aldosterone-producing adenomas (APA) and 20 paired samples of adjacent cortical tissue. Human adrenocortical cells HAC15 were used as in vitro model. Results: In our cohort of sporadic APAs, CRY1 resulted 1.7-fold [0.75–2.26] more expressed (p = 0.016) within the main node compared to adjacent cortical tissue, while CRY2 showed a 20% [0.80, 0.52–1.08] (p = 0.04) reduction in APA tissue. Type II HSD3B is the main isoform in APAs, being 317-fold [200–573] more expressed than HSD3B1. Both HSD3B isoforms are more expressed in APA compared with paired adjacent cortex, 5.7 (p < 0.001) and 3.5-fold (p = 0.001) respectively. Notably, HSD3B1 is significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. In HAC15 cells, angiotensin II (AngII) stimulation causes the upregulation of CRY1 (1.7 ± 0.25-fold, p < 0.001) at 6 hours and the downregulation of CRY2 (1.6 ± 0.1-fold, p < 0.001) at 12 hours, through activation of type 1 AngII receptor. Independent silencing of CRY1 and CRY2 determines a mild upregulation of HSD3B2, whereas it does not influence HSD3B1 expression. Conclusions: We demonstrated the potential role of CRY1 and CRY2 in the adrenal cell physiology and in the regulation of aldosterone secretion, considering that these genes are AngII-regulated and show a differential expression in APAs when compared with the adjacent adrenal cortex.