Department of Pathology and Laboratory Medicine, The Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Division of Kidney Diseases and Hypertension, Warren Alpert Medical School of Brown University, Providence, RI, USA.
J Steroid Biochem Mol Biol. 2021 Nov;214:105988. doi: 10.1016/j.jsbmb.2021.105988. Epub 2021 Aug 28.
11β-Hydroxysteroid dehydrogenase (11β-HSD)-dependent conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone are essential in regulating transcriptional activities of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Inhibition of 11β-HSD by glycyrrhetinic acid metabolites, bioactive components of licorice, causes sodium retention and potassium loss, with hypertension characterized by low renin and aldosterone. Essential hypertension is a major disease, mostly with unknown underlying mechanisms. Here, we discuss a putative mechanism for essential hypertension, the concept that endogenous steroidal compounds acting as glycyrrhetinic acid-like factors (GALFs) inhibit 11β-HSD dehydrogenase, and allow for glucocorticoid-induced MR and GR activation with resulting hypertension. Initially, several metabolites of adrenally produced glucocorticoids and mineralocorticoids were shown to be potent 11β-HSD inhibitors. Such GALFs include modifications in the A-ring and/or at positions 3, 7 and 21 of the steroid backbone. These metabolites may be formed in peripheral tissues or by gut microbiota. More recently, metabolites of 11β-hydroxy-Δ4androstene-3,17-dione and 7-oxygenated oxysterols have been identified as potent 11β-HSD inhibitors. In a living system, 11β-HSD isoforms are not exposed to a single substrate but to several substrates, cofactors, and various inhibitors simultaneously, all at different concentrations depending on physical state, tissue and cell type. We propose that this "cloud" of steroids and steroid-like substances in the microenvironment determines the 11β-HSD-dependent control of MR and GR activity. A dysregulated composition of this cloud of metabolites in the respective microenvironment needs to be taken into account when investigating disease mechanisms, for forms of low renin, low aldosterone hypertension.
11β-羟类固醇脱氢酶（11β-HSD）依赖性地将皮质醇转化为可的松，以及将皮质酮转化为 11-去氢皮质酮，这对于调节盐皮质激素受体（MR）和糖皮质激素受体（GR）的转录活性是必不可少的。甘草次酸代谢物（甘草的生物活性成分）抑制 11β-HSD 会导致钠潴留和钾丢失，从而引起肾素和醛固酮水平降低的高血压。原发性高血压是一种主要疾病，其潜在机制大多未知。在这里，我们讨论了一种原发性高血压的潜在机制，即内源性甾体化合物作为甘草次酸类似物（GALFs）发挥作用的概念，它们抑制 11β-HSD 脱氢酶，使糖皮质激素诱导的 MR 和 GR 激活，从而导致高血压。最初，几种肾上腺产生的糖皮质激素和盐皮质激素的代谢物被证明是强效的 11β-HSD 抑制剂。这些 GALFs 包括甾体骨架 A 环和/或 3、7 和 21 位的修饰。这些代谢物可能在周围组织中形成，也可能由肠道微生物群形成。最近，11β-羟基-Δ4-雄烯-3,17-二酮和 7-氧化甾醇的代谢物已被鉴定为强效的 11β-HSD 抑制剂。在活系统中，11β-HSD 同工酶不会暴露于单一底物，而是同时暴露于几种底物、辅助因子和各种抑制剂，其浓度因物理状态、组织和细胞类型而异。我们提出，这种微环境中的类固醇和类甾体物质“云”决定了 11β-HSD 对 MR 和 GR 活性的依赖性控制。在研究疾病机制时，需要考虑到微环境中这种代谢物“云”的组成失调，这对于低肾素、低醛固酮型高血压尤为重要。
