GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma
GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma
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KCNJ5 突变的肾上腺醛固酮腺瘤中 GSTA1 表达与醛固酮水平相关
DOI：
10.1210/jc.2017-00950
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发表时间：
2018-03-01
影响因子：
5.8
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
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作者：
Li, Xintao;Wang, Baojun;Zhang, Xu
背景：KCNJ5突变是产生醛固酮的腺瘤（APAs）的主要原因。除KCNJ5突变外，APA的发生发展研究较少。
目的：研究除KCNJ5之外影响醛固酮分泌的其他机制。
患者和方法：采用Affymetrix基因芯片人类转录组阵列2.0对6对KCNJ5突变的、醛固酮分泌高低不同的APAs、5个非KCNJ5突变的APAs以及4个正常肾上腺进行检测。共研究了113个APA样本以探索谷胱甘肽 - S - 转移酶A1（GSTA1）的表达。利用H295R细胞验证GSTA1的功能。
结果：GSTA1是在高醛固酮KCNJ5突变的APAs中下调最显著的基因。与野生型KCNJ5的APAs相比，GSTA1在KCNJ5突变的APAs中也下调。相应地，突变的KCNJ5降低了GSTA1信使RNA和蛋白质的表达水平。无论是在野生型还是突变型KCNJ5的H295R细胞中，GSTA1过表达均抑制醛固酮分泌。添加依他尼酸或沉默GSTA1通过增加活性氧（ROS）、超氧化物、过氧化氢水平以及钙离子内流增加醛固酮分泌。转录因子NR4A1、NR4A2和CAMK1的表达以及细胞内钙离子通过抑制GSTA1显著上调。还原型NAD磷酸氧化酶抑制剂或过氧化氢清除剂或阻断钙调蛋白或钙通道可显著降低GSTA1受抑制细胞中的醛固酮分泌。
结论：（1）在KCNJ5突变的APAs中，GSTA1表达与醛固酮水平呈负相关；（2）GSTA1通过ROS和钙离子信号调节醛固酮分泌；（3）KCNJ5突变下调GSTA1表达，GSTA1过表达可逆转KCNJ5突变的肾上腺细胞中醛固酮的增加。
Context: KCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated.Objective: To investigate other mechanisms affecting aldosterone secretion apart from KCNJ5.Patients and Methods: Six pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip HumanTranscriptome Array 2.0. Atotal of 113APAsampleswere investigated to explore the expression of glutathione-S-transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1.Results: GSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells.Conclusions: (1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells.