Nuesing, R. M. and Treude, A. and Weissenberger, C. and Jensen, B. and Bek, M. and Wagner, Charlotte and Narumiya, S. and Seyberth, H. W. (2005) Dominant role of prostaglandin E-2 EP4 receptor in furosemide-induced salt-losing tubulopathy: A model for hyperprostaglandin E syndrome/antenatal Bartter syndrome. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 16 (8). pp. 2354-2362. ISSN 1046-6673, 1533-3450
Full text not available from this repository. (Request a copy)Abstract
Increased formation of prostaglandin E-2 (PGE(2)) 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 PGE(2) formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE(2) 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 PGI(2) 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 EN 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 EN receptor mediates PGE(2)-induced renin secretion and that EP1, EP3, and EN receptors all contribute to enhanced PGE(2)-mediated salt and water excretion in the HPS/aBS model.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | THICK ASCENDING LIMB; NEPHROGENIC DIABETES-INSIPIDUS; RAT-KIDNEY; CYCLOOXYGENASE-2 EXPRESSION; RENIN EXPRESSION; MESSENGER-RNA; MICE LACKING; MACULA DENSA; RENOVASCULAR HYPERTENSION; ANGIOTENSIN-II; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 May 2021 10:34 |
| Last Modified: | 03 May 2021 10:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/35829 |
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