Atrial natriuretic peptide counteracts aldosterone secretion by preventing acute angiotensin II-induced cAMP...

Aldosterone plays a key role in blood pressure and volume regulation. Enhanced aldosterone secretion contributes to cardiovascular and renal diseases. Therefore, inhibitors of aldosterone receptors and synthase are essential drugs for the treatment of hypertension and heart failure. Both adrenocorticotropic hormone (ACTH) and angiotensin II (AngII) acutely increase aldosterone release via cAMP and Ca²⁺-signalling, respectively. Atrial natriuretic peptide (ANP) prevents excessive aldosterone secretion from adrenal zona glomerulosa (ZG) cells. ANP reduces ACTH-stimulated aldosterone by enhancing cAMP degradation through cGMP-stimulated phosphodiesterase (PDE2A). It is not known whether PDE2A also participates in counteracting AngII-induced aldosterone secretion.

In this study, we established CRISPR/Cas9 based knockdown of PDE2A in primary ZG cells and measured aldosterone release and cAMP/protein kinase A (PKA) activity using ELISA and Förster resonance energy transfer (FRET) biosensors, respectively.

We first showed that inhibition of AngII-stimulated aldosterone by ANP is mediated by cGMP independently of AngII-stimulated Ca²⁺-transients. However, knockdown of PDE2A completely abolished the inhibitory effect of the ANP/cGMP pathway on AngII-stimulated aldosterone, suggesting a cAMP-dependent mechanism. Indeed, depletion of intracellular cAMP by PDE4 overexpression or by adenylyl cyclase inhibition prevented AngII-stimulated aldosterone. Strikingly, AngII acutely stimulated Ca²⁺-activated adenylyl cyclase to increase cAMP levels and PKA activity, which were almost completely blocked by ANP via PDE2A.

ANP/cGMP signalling effectively counteracts acute AngII-induced aldosterone secretion by activating PDE2A, which degrades AngII-stimulated cAMP and prevents PKA activation. This novel signalling pathway could be a target for new aldosterone-reducing drugs.