EP1and EP4receptors mediate prostaglandin E2actions in the microcirculation of rat kidney

Abstract

Vasodilator prostaglandin PGE₂protects 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 EP₄receptors was identified by RT-PCR in freshly isolated preglomerular microvessels; cultured preglomerular vascular smooth muscle cells (VSMC) had EP₁-variant and EP₄RNA but lacked EP₁. EP₂and 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 PGE₂on the EP₄receptor, with no inhibition of cAMP by EP₁receptors. Studies of cytosolic calcium concentration in cultured renal VSMC support an inhibitory role of EP₄during ANG II stimulation. In vivo renal blood flow (RBF) studies indicate that the EP₄receptor is the primary receptor mediating sustained renal vasodilation produced by PGE₂, whereas the EP₁receptor 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 EP₄receptor is the major receptor in preglomerular VSMC. EP₄mediates PGE₂-induced vasodilation in the rat kidney and signals through G_sproteins to stimulate cAMP and inhibit cytosolic calcium concentration.