Morineau Gilles, Sulmont Véronique, Salomon Remi, Fiquet-Kempf Beatrice, Jeunemaître Xavier, Nicod Jérôme, Ferrari Paolo
Assistance Publique Hopitaux de Paris, Biochemistry Laboratory, Hôpital St. Antoine, Paris.
J Am Soc Nephrol. 2006 Nov;17(11):3176-84. doi: 10.1681/ASN.2006060570. Epub 2006 Oct 11.
In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF + 5alphaTHF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11betaHSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11betaHSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11betaHSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects.
在盐皮质激素靶组织中，如肾脏的皮质集合管，2型11β-羟类固醇脱氢酶（11βHSD2）负责将皮质醇在周围组织中转化为可的松，从而保护盐皮质激素受体不被皮质醇不适当激活。HSD11B2基因的突变会导致表观盐皮质激素增多综合征，这是一种常染色体隐性遗传性高血压，其中皮质醇发挥强效盐皮质激素的作用。本文描述了六个新的家系，其HSD11B2基因发生突变，导致低钾性高血压，受影响个体的血浆醛固酮水平低且肾素水平低，提示为盐皮质激素性高血压。尿类固醇代谢产物分析显示皮质醇失活减少，尿四氢皮质醇和四氢可的松的比值（THF + 5αTHF）/THE在2.4至40之间，除一例之外所有病例的尿游离可的松几乎缺失。对这些表观盐皮质激素增多患者的HSD11B2基因进行遗传分析发现，四个家系中有明显的纯合点突变，一个家系中有复合杂合突变，另一个家系中有一个23bp的外显子插入，导致移码并破坏氨基酸序列。在HEK-293细胞中表达的突变体的表达研究显示11βHSD2酶活性显著降低或丧失。结合作者丰富的个人经验中的既往病例对这些病例进行了回顾，以强调11βHSD2在理解激素作用新生物学原理中的重要性，表明11βHSD2将糖皮质激素激素在局部代谢为无活性衍生物是干预以实现特定醛固酮调节作用的机制之一。
