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

PGE(2) is a potent stimulator of renin release. So far, the contribution of each of the four PGE(2) receptor subtypes (EP(1)-EP(4)) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE(2) on renin secretion rates (RSR) from isolated, perfused kidneys of EP(1)-/-, EP(2)-/-, EP(3)-/-, EP(4)-/-, and wild-type mice. PGE(2) concentration dependently stimulated RSR from kidneys of all four knockout strains with a threshold concentration of 1 nM in EP(1)-/-, EP(2)-/-, EP(3)-/-, and wild-type mice, whereas the threshold concentration was shifted to 10 nM in EP(4)-/- mice. Moreover, the maximum stimulation of RSR by PGE(2) at 1 microM was significantly reduced in EP(4)-/- (12.8-fold of control) and EP(2)-/- (15.9-fold) compared with wild-type (20.7-fold), EP(1)-/- (23.8-fold), and EP(3)-/- (20.1-fold). In contrast, stimulation of RSR by either the loop diuretic bumetanide or the beta-adrenoceptor agonist isoproterenol was similar in all strains. PGE(2) 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 EP(2)-/- as well as EP(4)-/- mice, vasodilatation at low PGE(2) concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatory component was pronounced in kidneys of EP(1) and EP(3) knockout mice, whereas in both genotypes the vasoconstriction at higher PGE(2) concentrations was markedly blunted. Our data provide evidence that PGE(2) stimulates renin release via activation of EP(2) and EP(4) receptors, whereas EP(1) and EP(3) 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, EP(1) and EP(3) receptors increasing, and EP(2) as well as EP(4) receptors, decreasing it.