WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production
2014
Primary aldosteronism(PA) is the main cause of
secondary hypertension, resulting from adrenal
aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/β-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased
aldosteroneproduction and ectopic differentiation of
zona glomerulosacells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced
aldosteronesecretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the
nuclear receptorsNURR1 and NUR77. Altogether, these data show that aberrant WNT/β-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.
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