Urinary concentrating function in mice lacking EP₃receptors for prostaglandin E₂

Abstract

The actions of prostaglandin (PG) E2 are mediated by four distinct classes of PGE2E-prostanoid (EP) receptors (EP1through EP4). However, the in vivo functions of the individual EP receptor subtypes have not been delineated. To study the functions of one of these subtypes, the EP3 receptor, we generated EP3-deficient (−/−) mice by gene targeting. EP3 −/− animals survived in expected numbers, reproduced, and had no obvious abnormalities in their major organ systems. Because the EP3 receptor is expressed at high levels in the renal medulla and cortical collecting duct, and because previous studies have suggested that the EP3 receptor might antagonize the effects of vasopressin in the distal nephron, we examined urinary concentrating functions in EP3−/− mice. Basal urine osmolality (UOsm) was similar in groups of EP3 −/− and wild-type (EP3 +/+) mice. However, after inhibition of endogenous PGE2 production by indomethacin, UOsm increased significantly in EP3 +/+ but not in EP3 −/− mice. Despite this insensitivity to acute inhibition of prostanoid production, EP3 −/− mice concentrated and diluted their urine normally in response to a series of physiological stimuli. This suggests that PGE2 acts through the EP3 receptor to modulate urinary concentrating mechanisms in the kidney, but these effects are not essential for normal regulation of urinary osmolality.

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

“…However, if multiple receptors mediate sensitization of sensory neurons in situ, then attempts to inhibit a single receptor to block the inflammatory actions of PGE 2 might be ineffective. Furthermore, although transgenic mice with knockouts of single EP receptor subtype have been developed (53)(54)(55)(56), the redundancy of EP receptor functions, which we have reported in the present study, could limit the value of these single receptor transgenic models of nociceptive transmission. Future studies using double knockout mice might be more appropriate in studying the mechanisms of pain and inflammation.…”

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

“…Because of its linkage to inhibitory G-protein (Gi) and its high levels of expression in renal medulla, the EP3 receptor was suggested as a candidate to mediate the actions of PGE 2 in opposing vasopressin-stimulated water flow (50), yet in a previous study, we found only subtle changes in urinary concentrating and diluting mechanisms in EP3-deficient mice (51). In these studies, we find that the absence of mPGES1 has no effect on urinary concentrating capacity.…”

Receptors and Signaling Mechanisms Required for Prostaglandin E2-Mediated Regulation of Mast Cell Degranulation and IL-6 Production

“…The generation of mice deficient in EP 1 , EP 2 , EP 3 , and EP 4 receptors has been previously reported (11)(12)(13)(14). All mice used were at least 8 wk old and were bred and maintained in specific pathogen-free animal facilities at the University of North Carolina (Chapel Hill, NC), in accordance with the Institutional Animal Care and Use Committee guidelines.…”