Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2
Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2
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DOI：
10.1172/jci4445
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发表时间：
1999-03-01
影响因子：
15.9
通讯作者：
Mullins, AJ
中科院分区：
文献类型：
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作者：
Kotelevtsev, Y;Brown, RW;Mullins, AJ
人类11 β-羟类固醇脱氢酶2型（11 β-HSD 2）缺乏导致表观盐皮质激素过量综合征，其中皮质醇异常占据盐皮质激素受体，导致钠潴留、低钾血症和高血压。然而，这种疾病通常不完全纠正皮质醇的抑制，这表明额外的和不可逆的变化，可能在肾脏。为了进一步研究这一点，我们生产了11 β-HSD 2基因靶向破坏的小鼠。纯合子突变小鼠（11 β-HSD 2（-/-））在出生时表现正常，但近似50%的小鼠表现出运动无力，并在48小时内死亡。男性和女性幸存者都能生育，但表现出低钾血症、低渗性多尿和皮质酮的明显盐皮质激素活性。年轻的成年11 β-HSD 2（-/-）小鼠有明显的高血压，平均动脉血压为146 +/- 2 mmHg，而野生型对照组为121 +/- 2 mmHg，杂合子为114 +/- 4 mmHg。肾单位远曲小管上皮细胞明显肥大增生。这些组织学变化不容易逆转盐皮质激素受体拮抗剂在成年期。因此，11 β-HSD 2（-/-）小鼠表现出了高血压的主要特征，为研究肾脏重置导致高血压的分子机制提供了独特的啮齿动物模型。
Deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11 beta-HSD2 gene. Homozygous mutant mice (11 beta-HSD2(-/-)) appear normal at birth, but similar to 50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11 beta-HSD2(-/-) mice are markedly hypertensive, with a mean arterial blood pressure of 146 +/- 2 mmHg, compared with 121 +/- 2 mmHg in wild-type controls and 114 +/- 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11 beta-HSD2(-/-) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension.