title: The PGE(2)-EP4 receptor is necessary for stimulation of the renin-angiotensin-aldosterone system in response to low dietary salt intake in vivo.
abstract: Increased cyclooxygenase-2 (COX-2) expression and PGE(2) synthesis have been shown to be prerequisites for renal renin release after Na(+) deprivation. To answer the question of whether EP4 receptor type of PGE(2) mediates renin regulation under a low-salt diet, we examined renin regulation in EP4(+/+), EP4(-/-), and in wild-type mice treated with EP4 receptor antagonist. After 2 wk of a low-salt diet (0.02% wt/wt NaCl), EP4(+/+) mice showed diminished Na(+) excretion, unchanged K(+) excretion, and reduced Ca(2+) excretion. Diuresis and plasma electrolytes remained unchanged. EP4(-/-) exhibited a similar attenuation of Na(+) excretion; however, diuresis and K(+) excretion were enhanced, and plasma Na(+) concentration was higher, whereas plasma K(+) concentration was lower compared with control diet. There were no significant differences between EP4(+/+) and EP4(-/-) mice in blood pressure, creatinine clearance, and plasma antidiuretic hormone (ADH) concentration. Following salt restriction, plasma renin and aldosterone concentrations and kidney renin mRNA level rose significantly in EP4(+/+) but not in EP4(-/-) and in wild-type mice treated with EP4 antagonist ONO-AE3-208. In the latter two groups, the low-salt diet caused a significantly greater rise in PGE(2) excretion. Furthermore, mRNA expression for COX-2 and PGE(2) synthetic activity was significantly greater in EP4(-/-) than in EP4(+/+) mice. We conclude that low dietary salt intake induces expression of COX-2 followed by enhanced renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss.
authors.affiliation: Institute of Clinical Pharmacology, Goethe Univ., Frankfurt am Main, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Pöschke
authors.forename: Niklas
authors.initials: N
authors.lastname: Kern
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects / Q000502:physiology; D004039:Diet, Sodium-Restricted; D015232:Dinoprostone / Q000378:metabolism*; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D017673:Sodium Chloride, Dietary; D014667:Vasopressins / Q000097:blood
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D009281:Naphthalenes; D010654:Phenylbutyrates; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017673:Sodium Chloride, Dietary; D014667:Vasopressins; D000450:Aldosterone; D012083:Renin; D015232:Dinoprostone; D011188:Potassium