The PGE₂-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.

Physiology and Pathophysiology of the Intrarenal Renin-Angiotensin System: An Update

“…80 Subsequently, a large body of experimental evidence demonstrated that PGE 2 derived from COX-2 serves as a dominant mechanism in mediating renin secretion from the JGA via EP 2 and EP 4 receptors which signal through the cAMP pathway. 81,82 Besides the JGA, the CD is another major site of both production and action of PGE 2 . Among the microdissected nephron segments, the highest amount of PGE 2 was detected in the CD.…”

E-type prostanoid receptor 4 (EP4) in disease and therapy

“…This response appears to be mediated by cAMP-dependent hyperpolarization and inhibition of Ca 2+ currents that paradoxically inhibit renin-containing granule exocytosis. In vivo, low salt diet stimulates kidney renin mRNA levels and plasma renin concentrations in wild-type mice but not in EP4 knock-out mice or in mice treated with the EP4 antagonist ONO-AE3-208 (Poschke et al, 2012). Similar results were obtained in mice treated with furosemide (Nusing et al, 2005; Facemire et al, 2011).…”

Regulación de la liberación de renina durante la hipertensión renovascular

“…In vivo, el aumento de la expresión de COX-2 y de la síntesis de prostaglandinas vasodilatadoras, en particular la PGE 2 y la PGI 2 , estimulan la liberación de renina. Ratones con deleción de los receptores EP2 -/-, EP4 -/e IP -/-, mostraron reducción significativa de la expresión de renina tras la administración de una dieta baja en NaCl durante una semana (30). Los receptores EP2, EP4e IP se acoplan a proteínas Gs y a la estimulación de la adenilato ciclasa 5 presente en las células secretoras de renina; la adenilato ciclasa cataliza la conversión de ATP en AMP cíclico (AMPc) que, a su vez, estimula la actividad de cinasas de proteínas como la PKA (31).…”