Bedeutung der EP-Rezeptoren in der Pathogenese des antenatalen Bartter-Syndroms/Hyperprostaglandin-E-Syndroms und ihre Funktion in der renalen Elektrolytregulation

Das aBS/HPS ist eine angeborene, autosomal-rezessiv vererbte Salzverlust-Tubulopathie, die zu schweren Entgleisungen des Wasser- und Elektrolythaushaltes führt und unbehandelt tödlich verläuft. Systemisch kommt es unter anderem zu einer exzessiv gesteigerten PGE2-Synthese. Diese stellt eine Schlüsse...

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Bibliographic Details
Main Author: Treude, Antje
Contributors: Heldmaier, Gerhard (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2007
Biologie
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Table of Contents: Increased formation of PGE2 is a key part of antenatal Bartter syndrome/ hyperprostaglandin E syndrome (aBS/HPS), a renal disease characterized by NaCl wasting, water loss and hyper-reninism. Inhibition of PGE2 formation by COX 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 cotransporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wildtype mice (WT) and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-) we determined the effect of chronic furosemide administration (7 days) on urine output, sodium and potassium excretion and renin secretion. Further, we analyzed furosemide-induced diuresis and renin activity 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-/-. Compared to WT, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration (PRC) was significantly decreased in EP4-/- and to a lesser degree also in IP-/-. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, PRC, diuresis and sodium excretion seen in EP4-/-. The GFR in EP4-/- mice was not changed compared to WT, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. Our 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. In summary, our data indicate that inhibition of different EP receptors can decrease furosemide-induced diuresis to different extents. This may reflect the contribution of individual EP receptors to the blockade of salt and water reabsorption and to the support of secretion, respectively. Concluding from our findings we postulate that the EP4 receptor represents the dominant PGE2 receptor in pathogenesis of HPS/aBS. We presume EP4 antagonists as valuable drugs to treat furosemide-like salt losing tubulopathies such as HPS/aBS. The pharmacological effect may be similar to the application of COX inhibitors, however, EP4 receptor antagonists represent a more specific approach most likely combined with less adverse effects. EP4 receptor agonists and antagonists might be also valuable tools to stimulate or to decrease diuresis.