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Dominant Role of Prostaglandin E₂ EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy: A Model for Hyperprostaglandin E Syndrome/Antenatal Bartter Syndrome

Rolf M. Nüsing^*,, Antje Treude^*,, Christian Weissenberger^*, Boye Jensen, Martin Bek, Charlotte Wagner^||, Shuh Narumiya^¶ and Hannsjörg W. Seyberth^*

^* Department of Pediatrics, Philipps University, Marburg, Germany; Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany; Department of Physiology and Pharmacology, University of Southern Denmark-Odense, Odense, Denmark; Medizinische Klinik und Poliklinik D, Universität Münster, Münster, Germany; ^|| Institute of Physiology, University of Regensburg, Regensburg, Germany; and ^¶ Department of Pharmacology, Medical School Kyoto University, Kyoto, Japan

Address correspondence to: Dr. Rolf M. Nüsing, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt 60590, ermany. Phone: +49-69-63017676; Fax: +49-69-63017636; E-mail: r.m.nuesing{at}med.uni-frankfurt.de

Received for publication July 15, 2004. Accepted for publication May 17, 2005.

Increased formation of prostaglandin E₂ (PGE₂) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE₂ formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE₂ in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE₂ receptors (EP1^–/–, EP2^–/–, EP3^–/–, and EP4^–/–), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI₂ receptors (IP^–/–). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1^–/–, EP3^–/–, and EP4^–/– mice. Compared with WT mice, no difference was observed in EP2^–/– and IP^–/– mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4^–/– mice and to a lesser degree also in IP^–/– mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4^–/– mice. The GFR in EP4^–/– mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4^–/– mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE₂-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE₂-mediated salt and water excretion in the HPS/aBS model.

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