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

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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.