Molecular mechanisms and (patho)physiological relevance of the regulation of adrenal aldosterone by cardiac natriuretic peptides

肾上腺激素醛固酮在生理上维持体内盐和水的稳态中起着关键作用。它刺激肾钠重吸收，从而预防和补偿血容量减少和动脉低血压。醛固酮分泌失调，增加导致钠潴留，低钾血症和动脉高血压。事实上，原发性醛固酮增多症（PA）是继发性动脉高压最常见的内分泌原因。与原发性高血压相比，PA引起更多的终末器官损伤，并与心血管疾病发病率增加相关，包括慢性心力衰竭（HF）、卒中、非致命性心肌梗死和房颤。此外，充血性心力衰竭患者常伴有高醛固酮水平，这会损害预后。高醛固酮的不良影响不仅与肾钠水潴留有关，而且与这种激素对心脏、血管系统、肾脏和免疫细胞的直接影响有关。血管紧张素II和促肾上腺皮质激素（ACTH）是肾小球（ZG）醛固酮分泌的主要体液刺激物，并额外增强ZG细胞生长。相反，外源性合成心钠素（ANP）在体外和体内有效地抑制基线和刺激的醛固酮释放。这表明内源性心脏激素介导心脏和肾上腺之间的内分泌通讯，以生理上调节醛固酮分泌和ZG细胞生长，从而调节血压/容量。此外，ANP对醛固酮释放的这种抑制作用可以（以相互的方式）减轻高血压和缺血性心脏重构和炎症。为了剖析这种“双向”心脏-肾上腺轴的分子基础和功能意义，我们的项目将联合收割机结合原代培养的牛和小鼠ZG细胞，新的遗传小鼠模型和PA患者样本的研究。小鼠模型包括具有ANP受体和选择性受体后信号传导分子的肾上腺ZG细胞限制性破坏（KO）的小鼠。我们的项目将有助于更好地了解调节醛固酮分泌的途径和分子机制，并促进开发用于心血管和肾脏保护的醛固酮调节药物。

The adrenal hormone aldosterone has a critical role in the physiological maintenance of body salt and water homeostasis. It stimulates renal sodium reabsorption, which prevents and compensates hypovolemia and arterial hypotension. Dysregulated, increased aldosterone secretion leads to sodium retention, hypokalemia and arterial hypertension. In fact, primary aldosteronism (PA) is the most common endocrine cause of secondary arterial hypertension. Compared with essential hypertension, PA causes more end-organ damage and is associated with excess cardiovascular morbidity, including chronic heart failure (HF), stroke, nonfatal myocardial infarction, and atrial fibrillation. Moreover, patients with congestive HF often present with high aldosterone levels, which impairs prognosis. The adverse impact of high aldosterone is not only related to renal sodium-water retention but also to direct effects of this hormone on the heart, vasculature, kidney and immune cells. Angiotensin II and the adrenocorticotropic hormone (ACTH) are the main humoral stimulators of zona glomerulosa (ZG) aldosterone secretion and additionally enhance ZG cell growth. Conversely, exogenous synthetic atrial natriuretic peptide (ANP) potently inhibits baseline and stimulated aldosterone release in vitro and in vivo. This suggests that the endogenous cardiac hormone mediates an endocrine communication between the heart and the adrenal gland to physiologically moderate aldosterone secretion and ZG cell growth and thereby blood pressure/volume. Moreover, such inhibitory effects of ANP on aldosterone release could (in reciprocal way) attenuate hypertensive and ischemic cardiac remodeling and inflammation. To dissect the molecular basis and functional implications of this “bidirectional” heart-adrenal axis, our project will combine studies of primary cultured bovine and murine ZG cells, novel genetic mouse models and samples from patients with PA. The mouse models include mice with adrenal ZG cell restricted disruption (KO) of the ANP receptors, and of selective post-receptor signalling molecules. Our project will contribute to a better understanding of the pathways and molecular mechanisms regulating aldosterone secretion and can foster the development of aldosterone-moderating drugs for cardiovascular and renal protection.