Na + -Retaining Action of COX-2 (Cyclooxygenase-2)/EP 1 Pathway in the Collecting Duct via Activation of Intrarenal Renin-Angiotensin-Aldosterone System and Epithelial Sodium Channel

Abstract

Background: The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E 2 as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E 2 /EP 1 signaling for the regulation of Na + hemostasis during Na + depletion. Methods: Mice with Aqp2Cre-driven deletion of COX-2 (COX-2 fl/fl Aqp2Cre + ) or the EP 1 subtype (EP 1 fl/fl Aqp2Cre + ) were generated and the Na + -wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E 2 -induced local renin response were analyzed in primary cultured mouse inner medullary CD cells. Results: Following 28-day LS intake, COX-2 fl/fl Aqp2Cre + mice exhibited a higher urinary Na + excretion and lower cumulative Na + balance, accompanied with suppressed intrarenal renin, AngII (angiotensin II), and aldosterone, expression of CYP11B2 (cytochrome P450 family 11 subfamily B member 2), and blunted expression of epithelial sodium channel subunits compared to floxed controls (COX-2 fl/fl Aqp2Cre − ), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E 2 stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP 1 as compared other EP subtypes. Subsequently, EP 1 fl/fl Aqp2Cre + mice largely recapitulated Na + -wasting phenotype seen in COX-2 fl/fl Aqp2Cre + mice. Conclusions: The study for the first time reports that CD COX-2/EP 1 pathway might play a key role in maintenance of Na + homeostasis in the face of Na + depletion, at least in part, through activation of intrarenal renin-angiotensin-aldosterone-system and epithelial sodium channel.