From the Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (T.T., K.Y.H.W., D.L.B., C.S.T., G.H.W., J.S.W., L.H.P.).
Division of Endocrinology and Metabolism, Rajavithi Hospital, Rangsit University, Bangkok, Thailand (T.T.).
Hypertension. 2020 Apr;75(4):1045-1053. doi: 10.1161/HYPERTENSIONAHA.119.13821. Epub 2020 Mar 11.
LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency () in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in mouse kidney tissues, aldosterone secretion from glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.
LSD1（赖氨酸特异性去甲基酶-1）是基因转录的一种表观遗传调节剂。人类 LSD1 风险等位基因和 LSD1 缺乏（）在小鼠中随着年龄的增长导致血压对盐的敏感性增加，从而在老年人中发展为盐敏感性高血压。然而，LSD1 与血压对盐敏感性之间的关系的机制仍然难以捉摸。在这里，我们表明 LSD1 基因型（在人类）和 LSD1 缺乏（在小鼠）在自由盐饮食期间导致类似的与血压升高和尿钾水平升高相关联，但醛固酮水平降低。因此，我们假设 LSD1 缺乏导致 MR（盐皮质激素受体）依赖性高血压状态。然而，在用 MR 拮抗剂 eplerenone 治疗的小鼠中进一步研究表明，高血压、低钾尿和白蛋白尿得到了显著改善，这表明 MR 的非配体依赖性激活是这种 LSD1 缺乏介导表型的根本原因。事实上，虽然在 小鼠肾脏组织中观察到 MR 和上皮钠通道表达水平增加，但球状带细胞的醛固酮分泌显著降低。总之，这些数据表明 LSD1 缺乏在自由盐方案期间导致 MR 的不适当激活和水平升高，并表明抑制 MR 途径是治疗人类 LSD1 风险等位基因携带者高血压的一种有用策略。
