Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome
Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome
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DOI：
10.1161/hypertensionaha.109.134973
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发表时间：
2009-10-01
期刊：
影响因子：
8.3
通讯作者：
Kenyon, Christopher J.
中科院分区：
文献类型：
--
作者：
Bailey, Matthew A.;Mullins, John J.;Kenyon, Christopher J.
库欣患者和健康对照受试者接受促肾上腺皮质激素(ACTH)的实验表明，短暂的肾钠滞留可能导致高血压的产生。在这里，我们使用选择性拮抗剂解剖糖皮质激素和糖皮质激素受体介导的途径，研究了慢性ACTH输注对成年雄性C57BL/6J小鼠肾脏钠处理的影响。小鼠经渗透微泵注入ACTH(2.5 mg/d)或生理盐水2周后麻醉，进行肾功能实验。ACTH引起血压升高，与上皮钠通道活性增强相关的部分钠排泄减少。单独给予螺内酯和RU38486可钝化对ACTH的升压反应和上皮钠通道活性的增加；联合使用盐皮质激素和糖皮质激素受体阻断剂来解决对ACTH过量的反应。饮食中钠的消耗也可以预防ACTH引起的高血压。远端肾单位钠重吸收增加的影响被Henle环钠-钾-氯共转运的下调所抵消。钠的排泄是长期正常的，但血压仍然很高；急性阻断V1受体和α1肾上腺素能受体的联合作用使血压恢复到控制值。综上所述，ACTH过量促进了肾脏对钠的重吸收，导致血压升高；糖皮质激素和盐皮质激素受体途径都参与其中。这些数据与下丘脑-垂体-肾上腺轴过度活动有关，如肥胖和慢性应激。(高血压。2009年；54：890-896。)
Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor-mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 mu g/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and alpha 1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress. (Hypertension. 2009; 54: 890-896.)