WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production
Authors: Anne-Marie Lefrançois-Martinez
Bruno Ragazzon
Jérôme Bertherat
Antoine Martinez
Isabelle Sahut-Barnola
Seham Skah
Laurence Amar
Frédérique Tissier
Annabel Berthon
Michelina Plateroti
Guillaume Assié
Marie Batisse-Lignier
Pierre Val
Pierre-François Plouin
Sheerazed Boulkroun
Benoît Samson-Couterie
Coralie Drelon
Maria-Christina Zennaro
Hervé Lefèbvre
Journal: Human molecular genetics (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Primary aldosteronism; WNT/β-catenin signalling; adrenal aldosterone-producing adenomas; SFRP2; APA development
Affiliations: Clermont Université, Université Blaise Pascal, GReD, BP 10448, F-63000 Clermont-Ferrand, France.

Abstract:  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 aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, 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 receptors NURR1 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. 

Retracted: No

PubPeer comments:
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0229164 The University of Kentucky requested retraction of this article based on the findings of an institutional investigation. The institutional committee concluded that the article contains results that could not be validated with original data, and noted concerns about how experiments and results were documented in the laboratoryu2019s records. In our editorial review of this case, concerns were raised about the uniformity and lack of visible image details in the background areas of blot fragments reported in the western blot figures. In response to journal queries the authors provided cropped versions of the reported images with gray rather than white background and with improved visibility of faint bands in some cases. However, the images provided did not fully resolve the concerns about the integrity of these results. In addition, similarities were noted between u03b2-actin data reported in the following figure panels: Fig 1b, c, d Fig 3b, c, d Fig 4b, c Fig 4e, f Fig 5b, c The authors commented that the experiments in each set of figure panels used the same samples and the same experimental conditions, and so the same control blots were relevant for the indicated panels. In light of the above concerns and the recommendation by the University of Kentucky, the PLOS ONE Editors retract this article. NG disagrees with the retraction and stands by the integrity of the data and the validity of the reported results. ZZ did not agree with retraction. The other authors either did not reply or could not be reached. Reference 1.Gao N, Cheng S, Budhraja A, Liu E- H, Chen J, Chen D, et al. (2012) 3, 3u2032-Diindolylmethane Exhibits Antileukemic Activity In Vitro and In Vivo through a Akt-Dependent Process. PLoS ONE 7(2): e31783. https: doi.org 10.1371 journal.pone.0031783 ,