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Prostaglandin E₂ EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

¹Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark; and ²Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

Submitted 13 May 2005 ; accepted in final form 21 June 2005

PGE₂ and PGI₂ stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes and intracellular transduction mechanisms involved. Patch clamp was used to determine cell capacitance (C_m), current, and membrane voltage in response to PGE₂, EP2 and EP4 receptor agonists, and an IP receptor agonist. PGE₂ (0.1 µmol/l) increased C_m significantly, and the increase was abolished by intracellular application of the protein kinase A antagonist Rp-8-CPT-cAMPS. EP2-selective ligands butaprost (1 µmol/l), AE1–259-01 (1 nmol/l), EP4-selective agonist AE1–329 (1 nmol/l), and IP agonist iloprost (1 µmol/l) significantly increased C_m mediated by PKA. The EP4 antagonist AE3–208 (10 nmol/l) blocked the effect of EP4 agonist but did not alter the response to PGE₂. Application of both EP4 antagonist and EP2-antagonist AH-6809 abolished the effects of PGE₂ on C_m and current. EP2 and EP4 ligands stimulated cAMP formation in JG cells. PGE₂ rapidly stimulated renin secretion from superfused JG cells and diminished the membrane-adjacent granule pool as determined by confocal microscopy. The membrane potential hyperpolarized significantly after PGE₂, butaprost, AE1–329 and AE1–259 and outward current was augmented in a PKA-dependent fashion. PGE₂-stimulated outward current, but not C_m change, was abolished by the BK_Ca channel inhibitor iberiotoxin (300 nmol/l). EP2 and EP4 mRNA was detected in sampled JG cells, and the preglomerular and glomerular vasculature was immunopositive for EP4. Thus IP, EP2, and EP4 receptors are associated with JG cells, and their activation leads to rapid PKA-mediated exocytotic fusion and release of renin granules.

cyclooxygenase; capacitance; kidney; current; potential

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