Diastrophic Dysplasia Sulfate Transporter (SLC26A2) Is Expressed in the Adrenal Cortex and Regulates Aldosterone Secretion

Abstract

A rterial hypertension is a major cardiovascular risk factor that affects ≈30% to 60% of the population depending on the age group concerned.1 Pathogenic mechanisms underlying so-called essential hypertension are complex and include genetic and environmental, and vascular and hormonal factors. In community-based samples, increased aldosterone levels within the physiological range predispose to the development of high blood pressure. 2,3 On the far side of the spectrum, primary aldosteronism (PA), a form of endocrine hypertension, is characterized by inappropriately high aldosterone levels suppressing plasma renin concentrations, elevated blood pressure, and hypokalemia. PA is now recognized as the most common cause of secondary hypertension. 4,5 Aldosterone excess in the context of PA is relatively autonomous from angiotensin II stimulation and, thus, nonsuppressible by sodium loading. Aldosterone-producing adrenal adenomas or bilateral adrenal hyperplasia are responsible for the vast majority of cases, adenomas presenting more prominent renin system independency of aldosterone secretion. 5,6 Despite its high prevalence, to date, the genetic causes of PA have been elucidated mainly in rare familial forms of the disease. Few families have been identified with familial hyperaldosteronism type 1, also known as glucocorticoid remediable hyperaldosteronism. This disease is caused by unequal crossing over of the CYP11B1 (11β hydroxylase) and CYP11B2 (aldosterone synthase) and the formation of a 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 ...

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation

“…Sexual dimorphism in the mouse adrenal gland is well established, with clear sex differences in gene expression observed within the adrenal gland (86). Several previous mouse models of adrenal dysfunction have had varying results between the sexes (49,67,68,70,75,87). This further argues for a sex-dependent mechanism of adrenal regulation, possibly driven by androgens or estrogens.…”

Bilateral Idiopathic Adrenal Hyperplasia: Genetics and Beyond

“…Genetic variants in the REN gene were not Review associated with PRA or PRC, nor were SNPs at the CYP11B2 locus associated with circulating aldosterone concentrations. An independent analysis of the data on 1786 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort (KORA) had previously shown a highly significant genome-wide association of SNPs at chromosome 5q32 with the ARR [42]. Among the genes contained in the interval, the SLC26A2 locus codes for solute carrier family 26 member 2, a protein with known transport activity for sulfate and other cations.…”

Unanswered Questions in the Genetic Basis of Primary Aldosteronism

“…Regarding potential germline variants, whether genome-wide association studies (GWAS) or next-generation sequencing studies would be helpful remains to be determined. Prior GWAS studies have focused on aldosterone to renin ratio in a population-based cohort (not PA) [47] or candidate gene association with aldosterone levels [48].…”