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Publications

Journal Article Research Support, Non-U.S. Gov't Ppublish

PubMed: 42717871 DOI: 10.1161/HYPERTENSIONAHA.126.27506

Atrial Natriuretic Peptide Regulates Zona Glomerulosa Growth and Aldosterone Release.

Hypertension 83(11):e27506

Authors: Zihou Liu, Franziska Werner, Julia Sudnitsyna, Tamara Potapenko, Marco Abeßer, Viacheslav O Nikolaev, David T Breault, Dorothe Möllmann, Hideo A Baba, Celso E Gomez-Sanchez, Stefanie Hahner, Martin Fassnacht, Stefania Monterisi, Manuela Zaccolo, Michaela Kuhn

Affiliations

  • Institute of Physiology, Julius-Maximilians University (JMU) Würzburg, Germany (Z.L. F.W. J.S. T.P. M.A. M.K.).
  • Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (V.O.N.).
  • Division of Endocrinology, Boston Children's Hospital, MA (D.T.B.).
  • Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Germany (D.M. H.A.B.).
  • Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson (C.E.G.-S.).
  • Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital Würzburg, Germany (S.H. M.F.).
  • Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (S.M. M.Z.).

Abstract

BACKGROUND

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.

METHODS

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

RESULTS

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.

CONCLUSIONS

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.

MeSH

Cells, Hypertension, Zona Glomerulosa, Aldosterone, Growth, Cytochrome P-450 Cyp11B2, Homeostasis, Heart, Communication, Hyperaldosteronism, Diet, Herpes Zoster, Natriuretic Peptides, Atrial Natriuretic Factor, Hemodynamics