CASZ1: a promising factor modulating aldosterone biosynthesis and mineralocorticoid receptor activity
CASZ1: a promising factor modulating aldosterone biosynthesis and mineralocorticoid receptor activity
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DOI：
10.1038/s41440-022-01131-8
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发表时间：
2022-12
影响因子：
5.4
通讯作者：
K. Yokota;H. Shibata;I. Kurihara;H. Itoh;Masakatsu Sone
中科院分区：
文献类型：
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作者：
K. Yokota;H. Shibata;I. Kurihara;H. Itoh;Masakatsu Sone
高血压是心血管疾病的决定性危险因素。原发性醛固酮增多症（PA）是继发性高血压的一种典型形式，是导致难治性高血压的原因，并且比原发性高血压引起心血管并发症的风险更高。最近使用全基因组关联研究（GWASs）已经确定了几个参与高血压发病机制的基因。其中蓖麻锌指1（castor zinc finger 1, CASZ1）被认为通过调节醛固酮的作用参与高血压的病理生理。在2021年，利用液相色谱-串联质谱（LC-MS/MS）分析的生化方法，我们鉴定出CASZ1的异构体CASZ1b是一种新的矿物皮质激素受体（MR）共调节因子。我们进一步的分析表明，CASZ1b在MR靶点如肾小管细胞中与MR共表达，CASZ1蛋白水平的降低促进MR的醛固酮依赖性转录活性。此外，最近一项关于PA的GWAS研究发现CASZ1是PA相关基因，并证明CASZ1过表达抑制肾上腺细胞中的醛固酮生物合成。这些结果表明CASZ1通过醛固酮生物合成和MR转录活性双重机制在高血压和PA的病理生理中发挥关键作用。
Hypertension is the definitive risk factor for cardiovascular disease. Primary aldosteronism (PA), a typical form of secondary hypertension, is responsible for treatment-resistant hypertension and carries an even higher risk of causing cardiovascular complications than essential hypertension. Several genes involved in the pathogenesis of hypertension have been identified recently using genome-wide association studies (GWASs). Among these, castor zinc finger 1(CASZ1) is considered to be involved in the pathophysiology of hypertension via modulation of aldosterone action. In 2021, using a biochemical approach with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified CASZ1b, an isoform of CASZ1, as a novel mineralocorticoid receptor (MR) coregulator. Our further analysis revealed that CASZ1b is coexpressed with MR in MR targets such as kidney tubule cells, and that a decrease in CASZ1 protein levels promotes aldosterone-dependent transcriptional activity of MR. Further, a recent study of GWAS on PA identifiedCASZ1to be a PA-related gene and demonstrated that overexpression of CASZ1 suppresses aldosterone biosynthesis in adrenal cells. These results suggest CASZ1 plays a pivotal role in the pathophysiology of hypertension and PA via dual mechanisms: aldosterone biosynthesis and transcriptional activity of MR.