Role of Cryptochrome-1 and Cryptochrome-2 in Aldosterone-Producing Adenomas and Adrenocortical Cells.

Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (), the murine counterpart to the human type I 3β-hydroxyl-steroid dehydrogenase () gene. In the present study, we evaluated the role of and genes, and their potential interplay with isoforms in adrenal pathophysiology in man. Forty-six sporadic aldosterone-producing adenomas (APAs) and 20 paired adrenal samples were included, with the human adrenocortical cells HAC15 used as the in vitro model. In our cohort of sporadic APAs, expression was 1.7-fold [0.75⁻2.26] higher ( = 0.016), while showed a 20% lower expression [0.80, 0.52⁻1.08] ( = 0.04) in APAs when compared with the corresponding adjacent adrenal cortex. Type II 3β-hydroxyl-steroid dehydrogenase () was 317-fold [200⁻573] more expressed than , and is the main isoform in APAs. Both dehydrogenases were more expressed in APAs when compared with the adjacent cortex (5.7-fold and 3.5-fold, respectively, < 0.001 and = 0.001) and was significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. Treatment with angiotensin II (AngII) resulted in a significant upregulation of (1.7 ± 0.25-fold, < 0.001) at 6 h, and downregulation of at 12 h (0.6 ± 0.1-fold, < 0.001), through activation of the AngII type 1 receptor. Independent silencing of and genes in HAC15 cells resulted in a mild upregulation of without affecting expression. In conclusion, our results support the hypothesis that and , being AngII-regulated genes, and showing a differential expression in APAs when compared with the adjacent adrenal cortex, might be involved in adrenal cell function, and in the regulation of aldosterone production.