Atrial Natriuretic Peptide Regulates Zona Glomerulosa Growth and Aldosterone Release

The cardiac hormone ANP (atrial natriuretic peptide) maintains intravascular volume homeostasis through coordinated endothelial and renal effects. Since in vitro studies suggested that this circuit involves the inhibition of adrenal aldosterone release, here we investigated whether ANP indeed mediates endocrine heart-to-adrenal communication in vivo.

Mouse models with zona glomerulosa (ZG)-restricted deletion knockout of the ANP receptor, GC-A (guanylyl cyclase-A), or the downstream cyclic GMP-stimulated PDE (phosphodiesterase) 2A were established through Cre/LoxP technology.

Immunoblots and immunohistochemistry demonstrated high expression of GC-A and PDE2A in ZG cells. Cell-specific deletion of GC-A led to mildly expanded ZG, with more aldosterone synthase-expressing cells and elevated plasma aldosterone. While in control mice a high-salt diet reduced ZG thickness and aldosterone production, in their ZG GC-A knockout littermates these responses were blunted, provoking hypervolemic hypertension. Notably, ZG PDE2A knockout mice did not exhibit such alterations. In cultured human adrenal cells, ANP counteracted the stimulatory effects of Angiotensin II on aldosterone synthase expression and cell proliferation pathways through activation of cGMP-dependent protein kinase I. Notably, in human aldosterone-producing adrenal adenomas, the expression of GC-A was markedly lower than in healthy adrenal cortical tissue, suggesting reduced ANP/GC-A signaling in the tumor cells.

ANP-mediated heart-adrenal communication moderates ZG cell growth and aldosterone release and participates in the inhibitory effects of dietary salt/volume load. Conversely, impaired ANP/cGMP signaling leads to excessive ZG cell growth and aldosterone production. Reinforcing this pathway with novel antibody- or peptide-based therapies may benefit patients with hyperaldosteronism and resistant hypertension.