Untersuchungen zur Cyclooxygenase-abhängigen Nephrogenese bei der Maus

Die Einnahme von NSAIDs während der Schwangerschaft, speziell im 3. Trimenon, stellt beim Menschen ein erhebliches Problem für die fetale Nierenentwicklung dar. Zahlreiche tierexperimentelle Studien haben gezeigt, dass durch selektiven Knockout des COX-2-Gens, aber auch durch pharmakologische Inhi...

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Bibliographic Details
Main Author: Herud, Andreas
Contributors: Nüsing, Rolf Michael (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2009
Zentrum für Kinder- und Jugendmedizin
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Table of Contents: The intake of NSAIDs during pregnancy, especially in the 3rd trimenon, poses a great problem for human beings referring to the fetal renal developement. Several research results from animal tests have shown, that by selectiv knockout of the COX-2-gen, but also by pharmacological inhibition of the cyclooxygenase-2 by NSAIDs, nephrogenesis is strongly affected. The kidneys appeared macroscopically small and pale. Microscopically the kidneys appeared undeveloped with small, clustered and subcapsular glomeruli.Those glomeruli are lying in a thin cortex with cystical formations. Animals died after 4-5 months by the resulting renal failure. In order to demonstrate the impairing effects of NSAIDs, tests with several, in the clinic used selective COX-2-inhibitors, were made in this study. Another intention of this research was to get an answer to the question, by which mechanism or which receptor prostanoids affect nephrogenesis. Therefore agonists at the EP-2- and EP-4-receptor, as well as at the PPARγ- and PPARδ-receptor were used. An EP-4-antagonist in an EP-2-/- designed model showed its particular meaning. Additionally, the vasodillatativ effects of some NO-substances were proved. For agonists at EP-2-receptor as well as at EP-4-receptor is a from the dose dependent positive effect on the glomerulumvolumes seen, accordingly, there was no difference between the treated and wildtype animals. Thereby, the EP-4-receptor had the more precise effects. For the distances of the glomeruli from the renal capsule, which gives evidence to the cortex maturation, EP-4-receptor had just a partial effect. Thereby, the dose had no influence. From the NO-substances, NOC-12 was the one with minimal, but significant positive effects on the glomerulumvolumes. There was no significant difference between mice treated with Spermine NONOate and COX-2-/--mice, except those treated with 1000 μg/ml. The negative effects on the distances of the glomeruli from the renal capsule in this experiment were more severe as it is seen in a COX-2-/--mouse. Also the results of the PPARγ- and PPARδ-agonists are disillusioning. Neither Troglitazone nor GW 501516 had a positive effect on the glomerulumvolumes and the distances of the glomeruli from the renal capsule. The negative results in this experiment were as well more severe as it is seen in a COX-2-/--mouse. Except the mouse treated with GW501516, there was no difference between it and a COX-2-/--mouse in relation to the distances of the glomeruli from the renal capsule. The selective COX-2-inhibitor SC-236 has an from the dose and kind of application dependent result. This applies to the glomerulumvolumes as well as to the distances of the glomeruli from the renal capsule. Mice treated with 30 μg/ml SC-236, Parecoxib and Rofecoxib differ significantly from a COX-2-/--mouse in relation to the glomerulumvolumes. But this applies not to distances of the glomeruli from the renal capsule. Here Parecoxib and Rofecoxib have a partial effect, but Rofecoxib is the more potent one. By SC-236 it is seen a partial effect, but also a more severe effect as it is seen in a COX-2-/--mouse. The EP-4-antagonist showed in a EP-2-/- designed model a partial effect in both groups. In order to get the result of a COX-2-/--mouse, there probably are higher concentrations necessary. All in all the study has shown, that for regular renal maturation, especially for the glomerulumvolumes, the EP-2-receptor as well as the EP-4-receptor is very necessary. For the right distances of the glomeruli from the renal capsule, not only the EP-4-receptor seems to be important. There must be further mechanisms to be essential. The processes over the nuclear receptors PPARγ- and PPARδ seem not to be those, consequently this sector can be left. Also the vasodilatative mechanisms appear not to be the right ones. Maybe the Renin-Angiotensin-Aldosteron-System (RAAS) plays an important role and the key is just the right balance between the individual systems. This clearly should be kept in mind. The use of NSAIDs during the fetal renal developement, especially in the 3rd trimenon, can not be advised, because of the demonstrated heavy losses. They are rather contraindicated.