Stimulation of renin release by prostaglandin E2is mediated by EP2and EP4receptors in mouse kidneys

Abstract

PGE2is a potent stimulator of renin release. So far, the contribution of each of the four PGE2receptor subtypes (EP1–EP4) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE2on renin secretion rates (RSR) from isolated, perfused kidneys of EP1−/−, EP2−/−, EP3−/−, EP4−/−, and wild-type mice. PGE2concentration 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 PGE2at 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 β-adrenoceptor agonist isoproterenol was similar in all strains. PGE2exerted 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 PGE2concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatatory component was pronounced in kidneys of EP1and EP3knockout mice, whereas in both genotypes the vasoconstriction at higher PGE2concentrations was markedly blunted. Our data provide evidence that PGE2stimulates renin release via activation of EP2and EP4receptors, whereas EP1and EP3receptors appear to be without functional relevance in juxtaglomerular cells. In contrast, all four receptor subtypes are involved in the control of renal vascular tone, EP1and EP3receptors increasing, and EP2as well as EP4receptors, decreasing it.