Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E-2

The actions of prostaglandin (PG) E-2 are mediated by four distinct classes of PGE(2) E-prostanoid (EP) receptors (EP1 through EP4). However, the in v ivo functions of the individual EP receptor subtypes have not been delineat ed. To study the functions of one of these subtypes, the EP3 receptor, we g enerated EP3-deficient (-/-) mice by gene targeting. EP3 -/- animals surviv ed in expected numbers, reproduced, and had no obvious abnormalities in the ir major organ systems. Because the EP3 receptor is expressed at high level s in the renal medulla and cortical collecting duct, and because previous s tudies have suggested that the EP3 receptor might antagonize the effects of vasopressin in the distal nephron, we examined urinary concentrating funct ions in EP3 -/- mice. Basal urine osmolality (U-Osm) was similar in groups of EP3 -/- and wild-type (EP3 +/+) mice. However after inhibition of endoge nous PGE(2) production by indomethacin, U-Osm increased significantly in EP 3 +/+ but not in EP3 -/- mice. Despite this insensitivity to acute inhibiti on of prostanoid production, EP3 -/- mice concentrated and diluted their ur ine normally in response to a series of physiological stimuli. This suggest s that PGE(2) acts through the EP3 receptor to modulate urinary concentrati ng mechanisms in the kidney, but these effects are not essential for normal regulation of urinary osmolality.