title: A major role for the EP4 receptor in regulation of renin.
abstract: Prostaglandins have been implicated as paracrine regulators of renin secretion, but the specific pathways and receptor(s) carrying out these functions have not been fully elucidated. To examine the contributions of prostanoid synthetic pathways and receptors to regulation of renin in the intact animal, we used a panel of mice with targeted disruption of several key genes: cyclooxygenase-2 (COX-2), microsomal PGE synthases 1 and 2 (mPGES1, mPGES2), EP2 and EP4 receptors for PGE(2), and the IP receptor for PGI(2). To activate the macula densa signal for renin stimulation, mice were treated with furosemide over 5 days and renin mRNA levels were determined by real-time RT-PCR. At baseline, there were no differences in renin mRNA levels between wild-type and the various strains of mutant mice. Furosemide caused marked stimulation of renin mRNA expression across all groups of wild-type control mice. This response was completely abrogated in the absence of COX-2, but was unaffected in mice lacking mPGES1 or mPGES2. The absence of G(s)/cAMP-linked EP2 receptors had no effect on stimulation of renin by furosemide and there was only a modest, insignificant reduction in renin responses in mice lacking the IP receptor. By contrast, renin stimulation in EP4(-/-) mice was significantly reduced by ∼70% compared with wild-type controls. These data suggest that stimulation of renin by the macula densa mechanism is mediated by PGE(2) through a pathway requiring COX-2 and the EP4 receptor, but not EP2 or IP receptors. Surprisingly, mPGES1 or mPGES2 are not required, suggesting other alternative mechanisms for generating PGE(2) in response to macula densa stimulation.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, USA.
authors.forename: Carie S
authors.initials: CS
authors.lastname: Facemire
authors.forename: Mytrang
authors.initials: M
authors.lastname: Nguyen
authors.forename: Leigh
authors.initials: L
authors.lastname: Jania
authors.forename: William H
authors.initials: WH
authors.lastname: Beierwaltes
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Koller
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000818:Animals; D001794:Blood Pressure; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology*; D012083:Renin / Q000096:biosynthesis / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D013268:Stimulation, Chemical; D013686:Telemetry
chemical_list: D018076:DNA, Complementary; D004232:Diuretics; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; C578715:Slc12a1 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D012313:RNA; D005665:Furosemide; D051546:Cyclooxygenase 2; D012083:Renin; D015232:Dinoprostone