Gasparini Silvia, Peltekian Lila, McDonough Miriam C, Mitchell Chidera Ja, Hefti Marco, Resch Jon M, Geerling Joel C
Department of Neurology.
Department of Neuroscience and Pharmacology.
JCI Insight. 2024 Dec 6;9(23):e175087. doi: 10.1172/jci.insight.175087.
Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its prereceptor regulator, 11-β-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain and then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we used dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.
醛固酮分泌过多会增加患心脏病、中风、痴呆症和死亡的风险。醛固酮既会增加钠潴留，也会增加钠消耗，而钠消耗增加可能会使醛固酮增多症患者的终末器官损伤恶化。阻止这种增加可能会改善预后，但醛固酮诱导的钠食欲的行为机制仍不清楚。在啮齿动物中，我们之前鉴定出了醛固酮敏感神经元，这些神经元表达盐皮质激素受体及其前体调节因子11-β-羟基类固醇脱氢酶2（HSD2）。在本研究中，我们在人类大脑中鉴定出了HSD2神经元，然后使用小鼠模型评估它们在醛固酮诱导的盐摄入中的作用。首先，我们证实饮食中钠缺乏会增加醛固酮分泌、盐摄入和HSD2神经元活性。接下来，我们表明对HSD2神经元进行持续的化学遗传学刺激会导致盐摄入量大幅且特异性增加。最后，我们通过剂量反应研究和对HSD2神经元进行基因靶向消融，表明这些神经元对于醛固酮诱导的盐摄入是必需的。在人类大脑中鉴定出HSD2神经元，并确定它们在小鼠醛固酮诱导的盐摄入中的必要性，这增进了我们对食欲回路的理解，并突出了这一小群细胞作为调节饮食中钠的治疗靶点。
