Prostaglandin E2 Activates Basal EP4 Receptors to Stimulate Chloride Secretion Via Both cAMP and Calcium Mediated Pathways

Abstract

The renal collecting duct (CD) maintains salt (NaCl) balance by fine‐tuning NaCl excretion in response to dietary salt intake. Under conditions of high dietary salt intake (HDS), prostaglandin‐E2 (PGE‐2) production is enhanced and promotes NaCl excretion. The molecular mechanisms by which PGE‐2 works are not well defined. Under conditions of HDS, Na+ reabsorption is suppressed, and the regulation of Cl− secretion may predominate. The initial segment of the inner medullary CD (IMCD) is the only segment known to secrete Cl− under HDS. We used the mIMCD‐K2 cell line, a mouse cell line derived from the initial IMCD, to study the effects of PGE‐2 on Cl− transport in the IMCD.In mIMCD‐K2 cells, PGE‐2 activates basolateral EP‐4 receptors (EP‐4R) to increase Cl− secretion via both the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Ca2+ activated Cl− channels (CACC). EP‐4R activation enhances cAMP production which activates CFTR; unexpectedly, we found that EP4R activation also increases intracellular Ca2+ to stimulate CACC mediated Cl− secretion. We also determined that PGE‐2 stimulated secretion involves crosstalk between cAMP and Ca2+ signaling pathways in which intracellular Ca2+ influences CFTR activity and cAMP influences CACC activity. These two pathways, and the crosstalk between them, may represent a concerted mechanism by which PGE‐2 acts to enhance NaCl excretion under conditions of HDS.