title: Diastrophic dysplasia sulfate transporter (SLC26A2) is expressed in the adrenal cortex and regulates aldosterone secretion.
abstract: Elucidation of the molecular mechanisms leading to autonomous aldosterone secretion is a prerequisite to define potential targets and biomarkers in the context of primary aldosteronism. After a genome-wide association study with subjects from the population-based Cooperative Health Research in the Region of Augsburg F4 survey, we observed a highly significant association (P=6.78×10(-11)) between the aldosterone to renin ratio and a locus at 5q32. Hypothesizing that this locus may contain genes of relevance for the pathogenesis of primary aldosteronism, we investigated solute carrier family 26 member 2 (SLC26A2), a protein with known transport activity for sulfate and other cations. Within murine tissues, adrenal glands showed the highest expression levels for SLC26A2, which was significantly downregulated on in vivo stimulation with angiotensin II and potassium. SLC26A2 expression was found to be significantly lower in aldosterone-producing adenomas in comparison with normal adrenal glands. In adrenocortical NCI-H295R cells, specific knockdown of SLC26A2 resulted in a highly significant increase in aldosterone secretion. Concomitantly, expression of steroidogenic enzymes, as well as upstream effectors including transcription factors such as NR4A1, CAMK1, and intracellular Ca(2+) content, was upregulated in knockdown cells. To substantiate further these findings in an SLC26A2 mutant mouse model, aldosterone output proved to be increased in a sex-specific manner. In summary, these findings point toward a possible effect of SLC26A2 in the regulation of aldosterone secretion potentially involved in the pathogenesis of primary aldosteronism.
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstr. 1, D-80336 Munich, Germany. felix.beuschlein@med.uni-muenchen.de.
authors.forename: Ariadni
authors.initials: A
authors.lastname: Spyroglou
authors.forename: Tarik
authors.initials: T
authors.lastname: Bozoglu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rawal
authors.forename: Fabio
authors.initials: F
authors.lastname: De Leonardis
authors.forename: Christina
authors.initials: C
authors.lastname: Sterner
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
authors.forename: Luca
authors.initials: L
authors.lastname: Monti
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Richard
authors.initials: R
authors.lastname: Warth
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006929:Hyperaldosteronism / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008875:Middle Aged; D023421:Models, Animal; D011188:Potassium / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; C089651:SLC26A2 protein, human; C513264:Slc26a2 protein, mouse; D000076988:Sulfate Transporters; D000804:Angiotensin II; D000450:Aldosterone; D011188:Potassium
keywords: aldosterone to renin ratio; calcium signaling; genome-wide association study; knockout mice; primary hyperaldosteronism; solute carrier family 26 (sulfate transporter), member 2 protein, human