Mineralocorticoid receptor knockout mice:: Lessons on Na+ metabolism
Mineralocorticoid receptor knockout mice:: Lessons on Na+ metabolism
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DOI：
10.1046/j.1523-1755.2000.00965.x
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发表时间：
2000-04-01
影响因子：
19.6
通讯作者：
Schütz, G
中科院分区：
文献类型：
--
作者：
Berger, S;Bleich, M;Schütz, G
盐皮质激素受体（MR）以相等的亲和力结合醛固酮和糖皮质激素。在醛固酮靶组织中，如远端结肠的上皮细胞和肾脏中集合管的主细胞，MR通过酶11 β-羟基类固醇脱氢酶2型（110 β OHSD 2）的作用而免受糖皮质激素的影响，允许醛固酮特异性激活受体。然而，在缺乏11 β OHSD 2的MR表达细胞中，如大脑边缘系统的神经元，MR主要由糖皮质激素激活。MR敲除小鼠在出生后第二周死亡，在第8天显示出假性醛固酮减少症的症状，包括低钠血症、高钾血症、高肾性盐消耗和强活化的肾素-血管紧张素-醛固酮系统（RAAS）。阿米洛利敏感性上皮Na+通道（ENaC）的活性在结肠和肾脏中强烈降低，但三个ENaC亚基的mRNA丰度没有下调。每天皮下注射等渗NaCl溶液直至断奶，并持续口服NaCl供应导致MR敲除小鼠存活。氯化钠拯救的MR基因敲除小鼠显示出肾脏Na+排泄分数的强烈增强、高钾血症和持续强烈激活的RAAS。几乎没有肾ENaC活性。肾脏α ENaC mRNA丰度降低30%，而β ENaC和γ ENaC没有改变。
The mineralocorticoid receptor (MR) binds aldosterone and glucocorticoids with equal affinity. In aldosterone target tissues, like the epithelial cells of the distal colon and the principal cells of the collecting ducts in the kidney, the MR is protected from glucocorticoids by the action of the enzyme 11 beta-hydroxysteroid-dehydrogenase type 2 (110 beta OHSD2), allowing aldosterone to specifically activate the receptor. However, in MR-expressing cells, which lack 11 beta OHSD2, like the neurons of the limbic system in the brain, MR is mainly activated by glucocorticoids. MR knockout mice die in the second week after birth, showing at day 8 symptoms of pseudohypoaldosteronism with hyponatremia, hyperkalemia, high renal salt wasting, and a strongly activated renin-angiotensin-aldosterone system (RAAS). The activity of the amiloride-sensitive epithelial Na+ channel (ENaC) is strongly reduced in colon and kidney, but there is no down-regulation of the mRNA abundance of the three ENaC subunits. Daily subcutaneous injections of isotonic NaCl solution until weaning and continued oral NaCl supply lead to survival of the MR knockout mice. The NaCl-rescued MR knockout mice display a strongly enhanced fractional renal excretion of Na+, hyperkalemia, and a persistently strongly activated RAAS. There is almost no renal ENaC activity. The renal mRNA abundance of alpha ENaC is reduced by 30%, whereas beta ENaC and gamma ENaC are not altered.