Dokument: Der renale Phänotyp beim Very-Long-Chain Acyl-CoA Dehydrogenase- (VLCAD-) Mangel: Studien am VLCAD-/--Mausmodell
| Titel: | Der renale Phänotyp beim Very-Long-Chain Acyl-CoA Dehydrogenase- (VLCAD-) Mangel: Studien am VLCAD-/--Mausmodell | |||||||
| Weiterer Titel: | The renal phenotype in very-long-chain Acyl-CoA Dehydrogenase- (VLCAD-) Deficiency: Studies on the VLCAD-/--mouse model. | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=54052 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200902-110942-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Krogmann, Antonia [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Spiekerkötter, Ute [Gutachter] Keitel-Anselmino, Verena [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Der Very long-chain acyl-CoA Dehydrogenase (VLCAD)-Mangel ist die häufigste angeborene langkettige Fettsäurenoxidationsstörung und führt zu klinischen Symptomen in Zuständen mit erhöhtem Energiebedarf. Die Nieren und die Leber, als wichtige Organe für die Glukoneogenese, spielen vor allem unter den Bedingungen der gestörten Fettsäurenoxidation eine wichtige Rolle, um die Glukose Homöostase aufrechtzuerhalten. Es ist wenig bekannt, welche Auswirkungen eine gestörte mitochondriale Fettsäurenoxidation auf den renalen Stoffwechsel und die renale Funktion haben.
In der vorliegenden Studie untersuchten wir den renalen Metabolismus und den Nierenphänotyp im Modell der VLCAD-/--Maus. Die Untersuchungen erfolgten in drei Altersstufen der Maus, sowie unter verschiedenen metabolischen Zuständen, wie nach körperlicher Aktivität, nach Fasten und unter einer fettmodifizierten Diät. Zur Charakterisierung des Metabolismus gehörte die Oxidationsrate von Palmitoyl-CoA, um die Funktion des defizienten Enzyms bzw. enzymatische Kompensationsmechanismen zu definieren. Es erfolgte zudem die Bestimmung der Expressionsraten von Genen der β-Oxidation, des Kohlenhydratstoffwechsels, der Lipogenese, sowie die Quantifizierung von Glykogen und der Acylcarnitine im Nierengewebe. Zur Untersuchung der Nierenschädigung und Nierenfunktion wurden Marker des Nierenversagens bestimmt, sowie Funktionsbestimmungen antioxidativer Enzyme durchgeführt, da oxidativer Stress als Pathomechanismus beim VLCAD-Mangel diskutiert wird. Wichtige Ergebnisse dieser Analysen waren, dass - trotz niedriger Palmitoyl-CoA Oxidationsrate - das Nierengewebe der VLCAD-/--Mäuse keine Hinweise auf oxidativen Stress oder eine Nierenschädigung zeigte. Parallel zu Untersuchungen anderer Organe konnte in den Nieren jedoch eine verminderte Energieproduktion durch reduzierte Fettsäurenoxidation belegt werden. Im Gegensatz zu Herz und Muskel scheint die Niere weniger auf die Energie aus Fettsäuren angewiesen zu sein. Statt dessen entwickelt sie Mechanismen, um die Energieproduktion aus Kohlenhydraten zu sichern, was durch die signifikant erniedrigte Glykogenkonzentration in der Niere vor allem nach körperliche Aktivität belegt wurde. In verschiedenen Stresssituationen vor allem bei körperlicher Aktivität akkumulieren VLCAD-/--Mäuse keine langkettigen Acylcarnitine in den Nieren, wie dieses z.B. im Muskel oder im Herz nach körperlicher Aktivität der Fall ist. Zusammenfassend kann festgehalten werden, dass die Niere der VLCAD-/--Maus die Defizienz eines Enzyms der mitochondrialen Fettsäurenoxidation kompensieren kann. Die Nierenzellen können den Energiebedarf durch einen aktivierten Kohlenhydratmetabolismus im Rahmen von Ausdauertraining aufrechterhalten. Gleichzeitig fand sich eine Akkumulation langkettiger Fettsäurenmetabolite, deren langfristige Auswirkungen weiterhin unbekannt bleiben. VLCAD-/--Mäuse entwickeln keinen nephrologischen Phänotyp.Deficiency of the very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common inborn disorder of mitochondrial β-oxidation of long-chain fatty acids. Symptoms usually manifest in situations of increased energy demand. Kidney and liver, the main gluconeogenetic organs, play an important role in maintaining glucose homeostasis if β-oxidation is malfunctioning. Little is known about the consequences of a mitochondrial β-oxidation defects on renal metabolism and function. Therefore, we investigated how VLCAD-deficiency affects kidney function and kidney metabolism. We examined young and older mice, as well as mice in situations of normal and increased energy demand i.e. after exercise, fasting or under a supplemented fatty diet. To characterize the renal metabolism, we assessed the palmitoyl-CoA (C16-CoA) oxidation rate in the kidney of wild-type and VLCAD-/--mice as well as the expression of other dehydrogenases with overlapping substrate specificity. Renal damage and function were measured by the activity of antioxidant enzymes and by the expression of genes upregulated immediately prior to renal failure. Finally, renal glycogen content and acyl-carnitines were quantified as markers for impaired energy production from fatty acid oxidation. We were able to show that despite the very low oxidation rate of palmitoyl-CoA in renal mice tissue - the VLCAD-/--mice did not show any signs of oxidative stress or renal damage. In line with other organs we were able to identify a deminished energy production via fatty acid oxidation. Therefore, other than in heart and muscle tissue, the kidneys are not dependent on fatty acid oxidation. Instead the kidney develops mechanism to meet the energy demand via carbohydrate metabolism. This was shown by a decreased glycogen content in VLCAD-/--mice after physical exercise. Under situations of higher energy demand such as physical activity long-chain acylcarnitines do not accumulate in the kidneys of VLCAD-/--mice in contrast to heart and muscle tissue. In conclusion the kidneys of VLCAD-deficient mice are able to compensate the mitochondrial fatty acid oxidation defect. The activated carbohydrate metabolism meets the energy demand during physical stress. We also demonstrated accumulation of long chain fatty acids with unknown long-term effects. VLCAD-/--mice do not develop a nephrological phenotype. | |||||||
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| Rechtliche Vermerke: | Alle Studien wurden nach Genehmigung durch das Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen (Aktenzeichen 8.87-50.10.34.09.072) und nach den Richtlinien der Tierversuchskommission der Heinrich-Heine-Universität durchgeführt. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Sonstige Einrichtungen/Externe | |||||||
| Dokument erstellt am: | 02.09.2020 | |||||||
| Dateien geändert am: | 02.09.2020 | |||||||
| Promotionsantrag am: | 26.11.2019 | |||||||
| Datum der Promotion: | 20.08.2020 |
