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-L₁and in nerve terminals in the renal pelvic wall. Th₉-L₁DRG 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 μM) had no effect on SP release produced by PGE₂(0.14 μM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 μM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 μM) 12 ± 2 vs. 2 ± 1 and PGE₂, 9 ± 1 vs. 1 ± 0 pg/min. The SP release by butaprost and PGE₂was similarly blocked by the EP4 receptor antagonist AH-23848 (30 μM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 ± 100 and PGE₂·780 ± 100%·s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 μM L-161,982 and 10 μM AH-23848 blocked the ARNA responses to butaprost by 94 ± 5 and 78 ± 10%, respectively, and to PGE₂by 74 ± 16 and 74 ± 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 ± 5%. In conclusion, PGE₂increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.