Background:MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). 11βHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that MR maintains ENaC activity in the DCT2 and early connecting tubule in the absence of aldosterone.Methods:We studied AS (aldosterone synthase)-deficient (AS^−/−) mice, which were backcrossed onto the same C57BL6/J strain as kidney-specific MR knockout (KS-MR^−/−) mice. KS-MR^−/− mice were used to compare MR expression and ENaC localization and cleavage with AS^−/− mice.Results:MR was highly expressed along DCT2 through the cortical collecting duct (CCD), whereas no 11βHSD2 expression was observed along DCT2. MR signal and apical ENaC localization were clearly reduced along both DCT2 and CCD in KS-MR^−/− mice but were fully preserved along DCT2 and were partially reduced along CCD in AS^−/− mice. Apical ENaC localization and ENaC currents were fully preserved along DCT2 in AS^−/− mice and were not increased along CCD after low salt. AS^−/− mice exhibited transient Na⁺ wasting under low-salt diet, but administration of the MR antagonist eplerenone to AS^−/− mice led to hyperkalemia and decreased body weight with higher Na⁺ excretion, mimicking the phenotype of MR^−/− mice.Conclusions:Our results provide evidence that MR is activated in the absence of aldosterone along DCT2 and partially CCD, suggesting glucocorticoid binding to MR preserves sodium homeostasis along DCT2 in AS^−/− mice.

中文翻译：

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盐皮质激素受体拮抗剂在醛固酮缺乏的情况下引起尿钠排泄

背景：即使循环醛固酮水平不高，也建议顽固性高血压患者使用 MR（盐皮质激素受体）拮抗剂。虽然醛固酮可激活 MR 以增加上皮钠通道 (ENaC) 活性，但糖皮质激素也会激活 MR，但由 11βHSD2（2 型 11β-羟基类固醇脱氢酶）代谢。11βHSD2 从远曲小管 (DCT) 到集合管的表达水平不断增加。在这里，我们假设在没有醛固酮的情况下，MR 会维持 DCT2 和早期连接小管中的 ENaC 活性。 方法：我们研究了 AS（醛固酮合酶）缺陷型 (AS −/− ) 小鼠，这些小鼠与相同的 C57BL6/ ^J回交品系为肾脏特异性 MR 敲除 (KS-MR ^−/− ) 小鼠。KS-MR ^−/−小鼠用于与 AS ^−/−小鼠比较 MR 表达和 ENaC 定位和裂解。结果：MR 通过皮层集合管 (CCD) 沿 DCT2 高表达，而沿 DCT2 未观察到 11βHSD2 表达。在 KS-MR ^-/−小鼠中，MR 信号和心尖 ENaC 定位沿 DCT2 和 CCD 均明显减少，但沿 DCT2 完全保留，并在 AS ^-/−小鼠中沿 CCD 部分减少。^{在 AS −/−}小鼠中，顶端 ENaC 定位和 ENaC 电流沿着 DCT2 完全保留，并且在低盐后沿着 CCD 没有增加。AS ^−/−小鼠在低盐饮食下表现出短暂的 Na ^{+消耗，但对 AS 施用 MR 拮抗剂依普利酮−/−}小鼠导致高钾血症和体重下降，Na ⁺排泄量增加，模仿 MR ^−/−小鼠的表型。结论：我们的结果提供证据表明，在醛固酮缺失的情况下，MR 在 DCT2 和部分 CCD 上被激活，表明糖皮质激素与 MR 结合可维持 AS ^−/−小鼠中 DCT2 的钠稳态。