Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor
Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor
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DOI：
10.1038/s41440-022-00859-7
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发表时间：
2022-02
影响因子：
5.4
通讯作者：
Nao Kohata;I. Kurihara;K. Yokota;Sakiko Kobayashi;Ayano Murai-Takeda;Yuko Mitsuishi;Toshifumi Nakamura;Mitsuha Morisaki;T. Kozuma;Takuto Torimitsu;M. Kawai;H. Itoh
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作者：
Nao Kohata;I. Kurihara;K. Yokota;Sakiko Kobayashi;Ayano Murai-Takeda;Yuko Mitsuishi;Toshifumi Nakamura;Mitsuha Morisaki;T. Kozuma;Takuto Torimitsu;M. Kawai;H. Itoh
盐皮质激素受体（MR）及其配体醛固酮通过促进肾脏钠重吸收在控制血压中发挥核心作用。辅调节因子被募集来调节类固醇激素受体的活化。在我们以前的研究中，我们确定了几个新的候选人MR coregulators通过液相色谱串联质谱分析，使用生化方法。赖氨酸特异性脱甲基酶1（LSD 1）被确定为候选者。LSD 1和盐敏感性高血压之间的关系已被报道;然而，MR在这种情况下的作用在很大程度上是未知的。在这里，我们研究了LSD 1作为MR的辅助调节因子的功能。首先，使用HEK 293 F细胞的免疫共沉淀试验显示MR和LSD 1之间的特异性相互作用。染色质免疫沉淀研究证明LSD 1募集到上皮Na+通道（ENaC）的基因启动子，ENaC是MR的靶基因。通过用shRNA处理降低LSD 1表达增强ENaC和血清/糖皮质激素调节激酶1（MR的另一个靶基因）的激素激活，表明LSD 1是MR的辅阻遏物。肾特异性LSD 1基因敲除小鼠（LSD 1flox/LSD KSP-Cre小鼠）在高盐饮食后发生高血压，而醛固酮水平未升高，这可通过与MR拮抗剂螺内酯共同治疗来抵消。总之，我们的体外和体内研究表明，LSD 1是一个新发现的MR辅阻遏物。
Mineralocorticoid receptor (MR) and its ligand aldosterone play a central role in controlling blood pressure by promoting sodium reabsorption in the kidney. Coregulators are recruited to regulate the activation of steroid hormone receptors. In our previous study, we identified several new candidates for MR coregulators through liquid chromatography-tandem mass spectrometry analysis using a biochemical approach. Lysine-specific demethylase 1 (LSD1) was identified as a candidate. The relationship between LSD1 and salt-sensitive hypertension has been reported; however, the role of MR in this condition is largely unknown. Here, we investigated the functions of LSD1 as a coregulator of MR. First, a coimmunoprecipitation assay using HEK293F cells showed specific interactions between MR and LSD1. A chromatin immunoprecipitation study demonstrated LSD1 recruitment to the gene promoter of epithelial Na+channel (ENaC), a target gene of MR. Reduced LSD1 expression by treatment with shRNA potentiated the hormonal activation of ENaC and serum/glucocorticoid-regulated kinase 1, another target gene of MR, indicating that LSD1 is a corepressor of MR. In an animal study, mice with kidney-specific LSD1 knockout (LSD1flox/floxKSP-Cre mice) developed hypertension after a high-salt diet without elevation of aldosterone levels, which was counteracted by cotreatment with spironolactone, an MR antagonist. In conclusion, our in vitro and in vivo studies demonstrated that LSD1 is a newly identified corepressor of MR.