Dkk3 is a component of the genetic circuitry regulating aldosterone biosynthesis in the adrenal cortex.
Primary aldosteronism (PA, autonomous aldosterone production from the adrenal cortex) causes the most common form of secondary arterial hypertension (HT), which is also the most common curable form of HT. Recent studies have highlighted an important role of mutations in genes encoding potassium channels in the pathogenesis of PA, both in human disease and in animal models. Here, we have exploited the unique features of the hyperaldosteronemic phenotype of Kcnk3 null mice, which is dependent on sexual hormones, to identify genes whose expression is modulated in the adrenal gland according to the dynamic hyperaldosteronemic phenotype of those animals. Genetic inactivation of one of the genes identified by our strategy, dickkopf-3 (Dkk3), whose expression is increased by calcium influx into adrenocortical cells, in the Kcnk3 null background results in the extension of the low-renin, potassium-rich diet insensitive hyperaldosteronemic phenotype to the male sex. Compound Kcnk3/Dkk3 animals display an increased expression of Cyp11b2, the rate-limiting enzyme for aldosterone biosynthesis in the adrenal zona glomerulosa (ZG). Our data show that Dkk3 can act as a modifier gene in a mouse model for altered potassium channel function and suggest its potential involvement in human PA syndromes.
Institut de Pharmacologie Moléculaire et Cellulaire CNRS, Valbonne, France.
Abeer
A
El Wakil
Sascha
S
Bandulik
Nicolas
N
Guy
Saïd
S
Bendahhou
Maria-Christina
MC
Zennaro
Christof
C
Niehrs
Bernard
B
Mari
Richard
R
Warth
Jacques
J
Barhanin
Enzo
E
Lalli
D048868:Adaptor Proteins, Signal Transducing; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000450:Aldosterone; D002118:Calcium