PGE2 stimulates aldosterone release via cAMP/sPRR/β-catenin pathway in mouse inner medullary collecting duct cells

Increasing evidence showed the generation of aldosterone in the collecting duct (CD), a major site for the synthesis and action of prostaglandin E2 (PGE2). Both aldosterone and PGE2 are stimulated by Na+ depletion or K+ loading or angiotensin II. However, what happens first and the correlation between PGE2 and aldosterone in the CD remains obscure. PGE2 stimulates aldosterone release in the adrenal zona glomerulosa cells via E-prostanoid (EP) receptors by activating the cAMP/cAMP-responsive element-binding pathway. Here, we further tested the hypothesis that the synthesis of aldosterone is stimulated by PGE2 in CD cells and the underlying mechanism. In primary mouse inner medullary CD cells, PGE2 incubation significantly stimulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), (pro)renin receptor (PRR), and prorenin protein expression and upregulation of medium soluble PRR (sPRR), prorenin/renin, and cAMP levels, both of which were attenuated by the EP1 antagonist SC-19220 and the protein kinase C (PKC) inhibitor calphostin C. PGE2-induced release of aldosterone, prorenin/renin, and sPRR was also abolished by the protein kinase A inhibitor H89. Both a PRR antagonist PRO20 and β-catenin inhibitor ICG001 blunted PGE2 or sPRR-induced aldosterone and prorenin/renin secretion. Exogenous sPRR protein incubation not only stimulated the release of aldosterone and prorenin/renin but also reversed PF429242 (an inhibitor of subtilisin kexin isozyme-1, which can block endogenous sPRR generation)-attenuated aldosterone and prorenin/renin secretion. Therefore, we conclude that PGE2 increases CD aldosterone synthesis through the EP1 receptor via the PKC/cAMP/sPRR/β-catenin pathway.