Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1
Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1
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DOI：
10.1074/jbc.m115.657957
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发表时间：
2015-09-04
影响因子：
4.8
通讯作者：
Fagart, Jerome
中科院分区：
文献类型：
--
作者：
Amazit, Larbi;Le Billan, Florian;Fagart, Jerome
醛固酮通过激活盐皮质激素受体（MR）（核受体超家族成员）调节钠稳态。醛固酮增多症导致对肾脏、血管和心脏的有害影响。虽然甾体拮抗剂如螺内酯和依普利酮在临床上可用于治疗心血管疾病，但它们与几种副作用有关。Finerenone是一种新型非甾体类MR拮抗剂，目前正在两项IIb期临床试验中进行评估。在这里，我们的特点的分子机制的作用，非那利酮和螺内酯在几个关键步骤的MR信号通路。分子建模和诱变方法允许将Ser-810和Ala-773鉴定为非那利酮的高MR选择性的关键残基。此外，我们表明，与螺内酯（它激活导致严重早发性高血压的S810 L突变MR）相反，非利酮显示出严格的拮抗特性。醛固酮依赖性的磷酸化和MR的降解都受到非那利酮和螺内酯的抑制。然而，MR亚细胞分布的自动定量表明，非那利酮延迟醛固酮诱导的核积累的MR比螺内酯更有效。最后，染色质免疫沉淀试验显示，与螺内酯相反，非那利酮抑制MR、类固醇受体辅激活因子-1和RNA聚合酶II在SCNN 1A基因的调控序列处的结合，并且还显著减少基础MR和类固醇受体辅激活因子-1的募集，从而阐明了MR信号传导上的特异性和未识别的失活机制。总体而言，我们的数据表明，高效和选择性的MR拮抗剂非那利酮特异性损害MR信号通路的几个关键步骤，因此代表了一个有前途的新一代MR拮抗剂。
Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads to deleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displaysstrict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist.