EP₁and EP₄receptors mediate prostaglandin E₂actions in the microcirculation of rat kidney

Abstract

Vasodilator prostaglandin PGE(2) 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 EP(1), an EP(1)-variant, and EP(4) receptors was identified by RT-PCR in freshly isolated preglomerular microvessels; cultured preglomerular vascular smooth muscle cells (VSMC) had EP(1)-variant and EP(4) RNA but lacked EP(1). EP(2) and EP(3) receptors were undetectable in both vascular preparations. In studies of cell signaling, stimulation of cAMP by various receptor agonists is consistent with primary actions of PGE(2) on the EP(4) receptor, with no inhibition of cAMP by EP(1) receptors. Studies of cytosolic calcium concentration in cultured renal VSMC support an inhibitory role of EP(4) during ANG II stimulation. In vivo renal blood flow (RBF) studies indicate that the EP(4) receptor is the primary receptor mediating sustained renal vasodilation produced by PGE(2), whereas the EP(1) receptor elicits transient vasoconstriction. The EP(1)-variant receptor does not appear to possess any cAMP or cytosolic calcium signaling capable of affecting RBF. Collectively, these studies demonstrate that the EP(4) receptor is the major receptor in preglomerular VSMC. EP(4) mediates PGE(2)-induced vasodilation in the rat kidney and signals through G(s) proteins to stimulate cAMP and inhibit cytosolic calcium concentration.

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

“…In this study, we revealed the expression of the EP1 message within the glomeruli, mostly in the mesangial area, by in situ hybridization ( Figure 5), but its expression in renal microvessels was not apparent. Recently, it has been shown that the EP1 receptor is expressed in isolated preglomerular microvessels in rats by RT-PCR (34). Moreover, a recent report on immunohistochemical localization of EP receptors in human kidney revealed that the EP1 receptor is present in renal microvessels, including afferent and efferent arterioles (35).…”

Role of Prostaglandin E Receptor EP 1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

“…However, whether EP 1 on afferent arteriole smooth muscle cells really conveys proliferative signals remains to be determined, since vascular smooth muscle cells from arterioles no longer express EP 1 after cell culture, making the in vitro analysis difficult. 14 Furthermore, we could not determine whether EP 1 mRNA expression in the afferent arterioles differs between WKY and SHRSP, since EP 1 gene expression level in afferent arterioles was not high enough for detection by in situ hybridization. Using microdissection and RT-PCR, Purdy et al 14 reported that EP 1 expression can be detected in freshly isolated rat afferent arterioles.…”

“…14 Furthermore, we could not determine whether EP 1 mRNA expression in the afferent arterioles differs between WKY and SHRSP, since EP 1 gene expression level in afferent arterioles was not high enough for detection by in situ hybridization. Using microdissection and RT-PCR, Purdy et al 14 reported that EP 1 expression can be detected in freshly isolated rat afferent arterioles. The present study also showed that perivascular and interstitial fibrosis together with upregulation of TGF-␤ was attenuated by EP 1 A treatment.…”

“…[11][12][13][14] In rats, EP 1 , EP 3 , and EP 4 subtypes are present in afferent arteriole and glomerulus. 14,15 EP 4 exerts vasodilation in the afferent arteriole, whereas the vasoconstrictive effect of PGE 2 is presumed to be mediated by EP 1 or EP 3 .…”

Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy

“…All EP receptor types are expressed within the kidney in humans (19) and rodents (20). It has been shown that PGE 2 is involved in the regulation of renal blood flow, electrolyte and water reabsorption, and GFR, most likely by interaction with distinct EP receptor subtypes with specific tubular and vascular localization (19,(21)(22)(23)(24)(25)(26)(27). One may speculate that the detrimental effect of PGE 2 in patients with HPS/aBS is a consequence of enhanced blood flow or glomerular filtration, reduced electrolyte reabsorption in the distal tubule, or inhibition of arginine vasopressin-stimulated water reabsorption, which suggests an important and combined role for EP1, EP2, EP3, and EP4 receptor activation.…”