EP1 and EP4receptors mediate prostaglandin E2actions in the microcirculation of rat kidney

Abstract

Vasodilator prostaglandin PGE2 protects the kidney from excessive vasoconstriction during contraction of extracellular fluid volume and pathophysiological states. However, it is not yet clear which of the four known E-prostanoid (EP) receptors is localized to resistance vessels and mediates net vasodilation. In the present study, we assessed the presence, signal transduction, and actions of EP receptor subtypes in preglomerular arterioles of Sprague-Dawley rat kidneys. RNA encoding EP1, an EP1-variant, and EP4 receptors was identified by RT-PCR in freshly isolated preglomerular microvessels; cultured preglomerular vascular smooth muscle cells (VSMC) had EP1-variant and EP4 RNA but lacked EP1. EP2 and EP3receptors were undetectable in both vascular preparations. In studies of cell signaling, stimulation of cAMP by various receptor agonists is consistent with primary actions of PGE2 on the EP4 receptor, with no inhibition of cAMP by EP1receptors. Studies of cytosolic calcium concentration in cultured renal VSMC support an inhibitory role of EP4 during ANG II stimulation. In vivo renal blood flow (RBF) studies indicate that the EP4 receptor is the primary receptor mediating sustained renal vasodilation produced by PGE2, whereas the EP1 receptor elicits transient vasoconstriction. The EP1-variant receptor does not appear to possess any cAMP or cytosolic calcium signaling capable of affecting RBF. Collectively, these studies demonstrate that the EP4 receptor is the major receptor in preglomerular VSMC. EP4 mediates PGE2-induced vasodilation in the rat kidney and signals through Gs proteins to stimulate cAMP and inhibit cytosolic calcium concentration.