Diastrophic Dysplasia Sulfate Transporter (SLC26A2) Is Expressed in the Adrenal Cortex and Regulates Aldosterone Secretion
Diastrophic Dysplasia Sulfate Transporter (SLC26A2) Is Expressed in the Adrenal Cortex and Regulates Aldosterone Secretion
复制标题
DOI：
10.1161/hypertensionaha.113.02504
复制
发表时间：
2014-05-01
期刊：
影响因子：
8.3
通讯作者：
Beuschlein, Felix
中科院分区：
文献类型：
--
作者：
Spyroglou, Ariadni;Bozoglu, Tarik;Beuschlein, Felix
阐明导致自发性醛固酮分泌的分子机制是确定原发性醛固酮增多症潜在靶点和生物标志物的先决条件。在对来自奥格斯堡地区基于人群的合作健康研究F4调查的受试者进行全基因组关联研究后，我们观察到醛固酮与肾素比值与5 q32位点之间存在高度显著性关联（P=6.78x10（-11））。假设这个位点可能含有与原发性醛固酮增多症发病机制相关的基因，我们研究了溶质载体家族26成员2（SLC 26 A2），一种已知具有硫酸盐和其他阳离子转运活性的蛋白质。在小鼠组织中，肾上腺显示出SLC 26 A2的最高表达水平，其在血管紧张素II和钾的体内刺激下显著下调。SLC 26 A2的表达被发现是显着较低的醛固酮腺瘤相比，正常肾上腺。在肾上腺皮质NCI-H295 R细胞中，SLC 26 A2的特异性敲低导致醛固酮分泌的高度显著增加。同时，类固醇生成酶的表达，以及上游效应，包括转录因子，如NR 4A 1，CAMK 1，和细胞内Ca 2+含量，在敲低细胞上调。为了进一步证实SLC 26 A2突变小鼠模型中的这些发现，醛固酮输出被证明以性别特异性方式增加。总之，这些发现指向SLC 26 A2在调节可能参与原发性醛固酮增多症发病机制的醛固酮分泌中的可能作用。
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=6.78x10(-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 Ca2+ 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.