Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6
Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6
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DOI：
10.1038/nm.2061
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发表时间：
2010-01-01
期刊：
影响因子：
82.9
通讯作者：
Okamura, Hitoshi
中科院分区：
文献类型：
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作者：
Doi, Masao;Takahashi, Yukari;Okamura, Hitoshi
生物钟的故障与多种疾病的发病机制有关。我们发现，缺乏核心时钟成分Cryptochrome-1 （Cry1）和Cryptochrome-2 （Cry2）的小鼠（Cry-null小鼠）由于肾上腺合成矿化皮质激素醛固酮异常高而表现出盐敏感性高血压。通过对潜在原因的广泛研究，我们确定了iii型β -羟基类固醇脱氢酶（Hsd3b6）是小鼠中一种新的高血压危险因子。Hsd3b6仅在醛固酮产生细胞中表达，并受生物钟的转录控制。在ry-null小鼠中，Hsd3b6信使RNA和蛋白质水平高，导致3 β -羟基类固醇脱氢酶异构酶（3 β - hsd）酶活性显著增加，从而增加醛固酮的产生。这些数据表明Hsd3b6在昼夜节律紊乱与高血压的发展相关联的过程中处于关键地位。将这些发现转化为人类将需要对人类HSD3B1基因进行临床检查，我们发现该基因在功能上与小鼠Hsd3b6相似。
Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3 beta-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development of hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6.