ProjectDiscovery of a gene network associated with primary hyperaldosteronism

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The detection of secondary forms of hypertension is particularly important because it allows for targeted management of the underlying disease. Primary hyperendosteronism (PH) is the most common form of endocrine hypertension, caused in the majority of cases by dysregulated aldosterone secretion from adrenal cortex adenomas (APAs). Our studies, conducted in collaboration with Dr. Barhanin (University of Nice), have shown that the Task1 and Task3 potassium channels play a crucial role in regulating aldosterone secretion and adrenal cortex functional zonation in mice (Heitzmann's nucleus). et al., 2008; Penton et al., 2008 and 2012). We exploited the unique characteristics of the mouse model Kcnk3 (Task 1) KO to search for genes likely to modify their PA phenotype. We identified a group of genes closely associated with PA in a dynamic, sex- and hormone-dependent manner. Among these genes, in an initial series of studies, we focused our attention on Dkk3 (dickkopf3), encoding a particular member of the dickkopf family of Wnt signaling modulators. Inactivation of Dkk3 in mice Kcnk3 KO leads to the extension of the hyperaldosteronemic phenotype to the male sex and increased expression of the Cyp11b2, the enzyme limiting aldosterone biosynthesis in the adrenal gland, without affecting functional zonation (El Wakil et al., 2012). This data indicates that Dkk3 is a component of the genetic circuits regulating the expression of the Cyp11b2 and suggests that it could be involved in the pathogenesis of PA in humans.