Gu Huiying, Chen Zhe, Du Nicole, Yang Sisi, Yu Yongqi, Du Yansheng
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Boston Children's Hospital, Boston, MA 02115, USA.
Biology (Basel). 2024 Dec 22;13(12):1084. doi: 10.3390/biology13121084.
Hypertension remains a global health challenge due to its high prevalence and association with premature morbidity and mortality. Aldosterone, a mineralocorticoid hormone, and its receptor, the mineralocorticoid receptor (MR), are highly implicated in hypertension pathogenesis. Aldosterone synthase is the sole enzyme responsible for producing aldosterone in humans. We established transgenic mice carrying the human aldosterone synthase gene (cyp11B2) and showed dramatically increased levels of aldosterone in female hemizygotes. High-salt diets persistently increased blood pressure in these mice, and salt-induced hypertension was significantly ameliorated by reducing aldosterone levels via an aldosterone synthase inhibitor or blocking MR via an MR inhibitor. Since both hypertension and hyperaldosteronism specifically induce chronic kidney disease, in this model, we demonstrated that chronic high-salt diets induced hypertension in this mouse line and resulted in kidney inflammation and injury. Both the aldosterone synthase inhibitor and the MR antagonist markedly blocked high-salt-diet-mediated kidney injury. Thus, this transgenic mouse line can be used to study the pathogenic mechanisms underlying aldosterone and its receptor and to screen therapeutic compounds for aldosterone-mediated hypertension and related complications, such as kidney disease, in humans.
由于高血压的高患病率以及与过早发病和死亡的关联，它仍然是一项全球性的健康挑战。醛固酮是一种盐皮质激素，其受体即盐皮质激素受体（MR），在高血压发病机制中具有高度相关性。醛固酮合酶是人体内负责生成醛固酮的唯一酶。我们构建了携带人醛固酮合酶基因（cyp11B2）的转基因小鼠，并发现雌性半合子小鼠体内醛固酮水平显著升高。高盐饮食持续升高这些小鼠的血压，而通过醛固酮合酶抑制剂降低醛固酮水平或通过MR抑制剂阻断MR，可显著改善盐诱导的高血压。由于高血压和醛固酮增多症均会特异性地诱发慢性肾脏病，在该模型中，我们证明慢性高盐饮食在这种小鼠品系中诱发了高血压，并导致肾脏炎症和损伤。醛固酮合酶抑制剂和MR拮抗剂均显著阻断了高盐饮食介导的肾脏损伤。因此，这种转基因小鼠品系可用于研究醛固酮及其受体的致病机制，并筛选针对人类醛固酮介导的高血压及相关并发症（如肾脏疾病）的治疗化合物。
