Activation of EP4 receptors contributes to prostaglandin E₂-mediated stimulation of renal sensory nerves

Abstract

.-Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E2 (PGE2) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th9-L1 and in nerve terminals in the renal pelvic wall. Th9-L1 DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 M) had no effect on SP release produced by PGE2 (0.14 M) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 M) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 M) 12 Ϯ 2 vs. 2 Ϯ 1 and PGE2, 9 Ϯ 1 vs. 1 Ϯ 0 pg/min. The SP release by butaprost and PGE2 was similarly blocked by the EP4 receptor antagonist AH-23848 (30 M). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 Ϯ 100 and PGE2 ⅐ 780 Ϯ 100% ⅐ s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 M L-161,982 and 10 M AH-23848 blocked the ARNA responses to butaprost by 94 Ϯ 5 and 78 Ϯ 10%, respectively, and to PGE2 by 74 Ϯ 16 and 74 Ϯ 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 Ϯ 5%. In conclusion, PGE2 increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers. EP3 receptors; cyclooxygenase-2; substance P; butaprost; L-161,982 PROSTAGLANDIN E 2 (PGE 2 ) is the major product of cyclooxygenase (COX)-induced metabolism of arachidonic acid in the kidney (3) and plays a critical role for normal renal function by its effects on renal microvasculature and urinary water and sodium excretion. In addition to its direct effects on tubular sodium and water reabsorption, our studies indicate that PGE 2 also modulates urinary sodium excretion by its effects on afferent renal nerves (25,27,29).The majority of the afferent renal nerves containing substance P and calcitonin gene-related peptide (CGRP) are located in the renal pelvic wall (28,33,54). These nerves are activated by increases in renal pelvic pressure of a magnitude, Ն3 mmHg (26, 30), seen during moderate volume expansion. The increase in afferent renal nerve activity (ARNA) produced by the increased renal pelvic pressure leads to a reflex decrease in efferent renal sympathetic nerve activity (ERSNA) and a diuresis and natriuresis, i.e., a renorenal reflex response (31).Among the various mechanisms activated by stretching the renal pelvic wall is induction of COX-2 leading to increased renal pelvic...

Involvement of Renal Sympathetic Nerve Activation on the Progression of Ischemic Acute Kidney Injury in the Mouse

“…Sympathetic nerves innervate the afferent and efferent juxtaglomerular arterioles and the interlobular arteries in the outer cortex of rabbit kidney and the afferent arterioles in the rat kidney (8). The tyrosine hydroxylase immunoreactivity is detected in the renal pelvic wall (19). In the present study, the glomerular tyrosine hydroxylase immunoreactivity was colocalized with synapsin I, a nerve terminal marker protein (Fig.…”

Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation

“…[1][2][3] Importantly, AT1-R has been located in the renal pelvic wall. 31 Although there is currently little information on the location of ETA-R in the renal pelvic wall, the presence of ETA-R in vascular smooth muscle layers throughout the kidney 35 suggests that these receptors are also found in the renal pelvic wall.…”

“…1,2,6,7,9,10 In brief, after anesthesia, renal pelvises dissected from the kidneys were placed in wells containing 400 L of HEPES buffer (pH 7.4), 37°C, containing indomethacin (0.14 mmol/L) to minimize the influence of endogenous PGE 2 on substance P release. Each well contained the pelvic wall from 1 kidney.…”

“…[1][2][3] Activation of these nerves by increases in renal pelvic pressure results in increases in afferent renal nerve activity (ARNA) leading to reflex decreases in efferent renal sympathetic nerve activity and diuresis and natriuresis, that is, a renorenal reflex response. 4 Among the various mechanisms activated by stretching the renal pelvic wall is induction of cyclooxygenase-2 resulting in increased renal pelvic synthesis of PGE 2 .…”

“…5,6 PGE 2 leads to activation of the cAMP-protein kinase A transduction pathway and a release of the neuropeptide substance P, which activates the afferent renal nerves by stimulating neurokinin-1 receptors in the renal pelvic area. 1,7,8 The responsiveness of the afferent renal nerves is enhanced by high-sodium diet and suppressed by low-sodium diet because of an interaction between prostaglandin (PG) E 2 (PGE 2 ) and angiotensin (Ang) II at the peripheral renal sensory nerve endings. 7,9,10 In conditions of high-sodium diet, characterized by low endogenous Ang II, 11 there is little or no inhibition of the PGE 2 -mediated activation of adenylyl cyclase.…”