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

BACKGROUND

The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E 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/EP signaling for the regulation of Na hemostasis during Na depletion.

METHODS

Mice with Aqp2Cre-driven deletion of COX-2 (COX-2Aqp2Cre) or the EP subtype (EPAqp2Cre) were generated and the Na-wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E-induced local renin response were analyzed in primary cultured mouse inner medullary CD cells.

RESULTS

Following 28-day LS intake, COX-2Aqp2Cre 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-2Aqp2Cre), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP as compared other EP subtypes. Subsequently, EPAqp2Cre mice largely recapitulated Na-wasting phenotype seen in COX-2Aqp2Cre mice.

CONCLUSIONS

The study for the first time reports that CD COX-2/EP 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.