Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome.

Abstract

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.

• Authors: Rolf M Nüsing, Antje Treude, Christian Weissenberger, Boye Jensen, Martin Bek, Charlotte Wagner, Shuh Narumiya, Hannsjörg W Seyberth
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 16 Issue 8 Pg. 2354-62 (Aug 2005) ISSN: 1046-6673 [Print] United States
• PMID: 15976003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Cyclooxygenase Inhibitors
• Diuretics
• Enzyme Inhibitors
• Prostaglandins E
• Ptger1 protein, mouse
• Ptger3 protein, mouse
• Ptger4 protein, mouse
• RNA, Messenger
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP1 Subtype
• Receptors, Prostaglandin E, EP3 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Salts
• Sodium Chloride, Dietary
• Sodium-Potassium-Chloride Symporters
• Symporters
• potassium-chloride symporters
• Sodium Chloride
• Furosemide
• Sodium
• Ribonucleases
• Renin
• Dinoprostone

Topics

• Actins (metabolism)
• Animals
• Bartter Syndrome (metabolism, pathology)
• Cyclooxygenase Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Diuresis
• Diuretics (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Furosemide (pharmacology)
• Glomerular Filtration Rate
• Kidney Tubules (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Models, Statistical
• Prostaglandins E (metabolism)
• RNA, Messenger (metabolism)
• Receptors, Prostaglandin E (metabolism, physiology)
• Receptors, Prostaglandin E, EP1 Subtype
• Receptors, Prostaglandin E, EP3 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Renin (metabolism)
• Ribonucleases (metabolism)
• Salts (metabolism, pharmacology)
• Sodium (metabolism)
• Sodium Chloride (pharmacology)
• Sodium Chloride, Dietary (pharmacology)
• Sodium-Potassium-Chloride Symporters (metabolism)
• Symporters (antagonists & inhibitors)
• Time Factors