Mineralocorticoid receptors: Distribution and activation
Mineralocorticoid receptors: Distribution and activation
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DOI：
10.1007/s10741-005-2344-2
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发表时间：
2005-01-01
影响因子：
4.6
通讯作者：
Funder, JW
中科院分区：
文献类型：
--
作者：
Funder, JW
矿化皮质激素受体（MR）以高亲和力结合矿化皮质激素和糖皮质激素（脱氧皮质酮=皮质酮>=醛固酮=皮质醇），存在于钠离子转运上皮（如肾、结肠）和非上皮组织（如心、脑）中。MR在醛固酮合成酶之前进化，这与它们在非上皮组织中作为高亲和力糖皮质激素受体的作用一致，基本上总是被正常水平的内源性糖皮质激素占据。在上皮组织中，11 β羟类固醇脱氢酶2型（11 β HSD2）允许醛固酮选择性地激活MR，通过将皮质醇转化为可的松和将NAD转化为NADH。11 β HSD2使细胞内皮质醇减少90%，达到醛固酮水平的10倍，因此当酶工作时，大多数上皮MR被占用但不被皮质醇激活。当细胞内氧化还原状态发生改变时——通过抑制11 β HSD2、产生活性氧或细胞内引入氧化谷胱甘肽（GSSG）——皮质醇从MR拮抗剂转变为MR激动剂。皮质醇的这种二价活性似乎是MR阻断治疗心力衰竭和原发性高血压疗效的基础，为MR阻断治疗不以醛固酮水平升高为特征的心血管疾病提供了理论依据。其更广泛的（病理）生理意义，特别是神经生物学，仍有待探索。
Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone >= aldosterone = cortisol), and are found in both Na+ transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain). MR evolved before aldosterone synthase, consistent with their acting in nonepithelial tissues as high affinity glucocorticoid receptors, essentially always occupied by normal levels of endogenous glucocorticoids. In epithelial tissues the enzyme 11 beta hydroxysteroid dehydrogenase Type 2 (11 beta HSD2) allows aldosterone to selectively activate MR, by converting cortisol to cortisone and NAD to NADH. 11 beta HSD2 debulks intracellular cortisol by 90%, to levels similar to 10-fold those of aldosterone, so that when the enzyme is operating most epithelial MR are occupied but not activated by cortisol. When intracellular redox state is changed-by inhibition of 11 beta HSD2, generation of reactive oxygen species, or intracellular introduction of oxidised glutathione (GSSG)-cortisol changes from an MR antagonist to an MR agonist. This bivalent activity of cortisol appears to underlie the therapeutic efficacy of MR blockade in heart failure (RALES, EPHESUS) and in essential hypertension, providing a rationale for MR blockade in cardiovascular disease not characterized by elevated aldosterone levels. Its wider (patho)physiologic implications, particularly for neurobiology, remain to be explored.