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Stimulation of renin release by prostaglandin E₂ is mediated by EP₂ and EP₄ receptors in mouse kidneys

¹Institute for Physiology, University of Regensburg, 93042 Regensburg; ³Department of Pediatrics, Philipps-University Marburg, 35033 Marburg, Germany; and ²Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

Submitted 5 March 2004 ; accepted in final form 23 April 2004

PGE₂ is a potent stimulator of renin release. So far, the contribution of each of the four PGE₂ receptor subtypes (EP₁–EP₄) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE₂ on renin secretion rates (RSR) from isolated, perfused kidneys of EP₁–/–, EP₂–/–, EP₃–/–, EP₄–/–, and wild-type mice. PGE₂ concentration dependently stimulated RSR from kidneys of all four knockout strains with a threshold concentration of 1 nM in EP₁–/–, EP₂–/–, EP₃–/–, and wild-type mice, whereas the threshold concentration was shifted to 10 nM in EP₄–/– mice. Moreover, the maximum stimulation of RSR by PGE₂ at 1 µM was significantly reduced in EP₄–/– (12.8-fold of control) and EP₂–/– (15.9-fold) compared with wild-type (20.7-fold), EP₁–/– (23.8-fold), and EP₃–/– (20.1-fold). In contrast, stimulation of RSR by either the loop diuretic bumetanide or the -adrenoceptor agonist isoproterenol was similar in all strains. PGE₂ exerted a dual effect on renal vascular tone, inducing vasodilatation at low concentrations (1 nmol/) and vasoconstriction at higher concentrations (100 nmol/) in kidneys of wild-type mice. In kidneys of EP₂–/– as well as EP₄–/– mice, vasodilatation at low PGE₂ concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatatory component was pronounced in kidneys of EP₁ and EP₃ knockout mice, whereas in both genotypes the vasoconstriction at higher PGE₂ concentrations was markedly blunted. Our data provide evidence that PGE₂ stimulates renin release via activation of EP₂ and EP₄ receptors, whereas EP₁ and EP₃ receptors appear to be without functional relevance in juxtaglomerular cells. In contrast, all four receptor subtypes are involved in the control of renal vascular tone, EP₁ and EP₃ receptors increasing, and EP₂ as well as EP₄ receptors, decreasing it.

renin secretion; renal vascular resistance; bumetanide; isolatedperfused mouse kidney

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