Dokument: Einfluss einer hypoosmotisch-induzierten Zellschwellung auf die intrazelluläre Zinkhomöostase in kultivierten Astrozyten
| Titel: | Einfluss einer hypoosmotisch-induzierten Zellschwellung auf die intrazelluläre Zinkhomöostase in kultivierten Astrozyten | |||||||
| Weiterer Titel: | Hypoosmotic swelling affects zinc homeostasis in cultured rat astrocytes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=50445 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20190814-080702-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Grünig, Carolin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. med. Häussinger, Dieter [Gutachter] Lang, Philipp [Gutachter] | |||||||
| Stichwörter: | Hepatische Enzephalopathie, Zink, hyoosmotische Astrozytenschwellung | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Zusammenfassung
Eine Astrozytenschwellung tritt im Verlauf verschiedener neurologischer Erkrankungen und bei Verletzungen des Gehirns auf. Bei der hepatischen Enzephalopathie (HE) nimmt die Astrozytenschwellung eine Schlüsselrolle in der Pathogenese ein. Die Schwellung von Astrozyten ist mit der Bildung von oxidativem/nitrosativem Stress assoziiert. Reaktive Stick- und Sauerstoffspezies (RNOS) können in unterschiedlichen Zelltypen eine Freisetzung proteingebundener Zinkionen (Zn2+) bewirken und darüber die Funktionen verschiedener Proteine, wie z.B. von Transkriptionsfaktoren, beeinflussen. Da die Bindung einiger Transkriptionsfaktoren an die DNA durch Zinkfingerdomänen vermittelt wird, kann eine Störung der Zinkhomöostase durch oxidativen/nitrosativen Stress die Gentranskription modulieren. In der vorliegenden Dissertation wurden Effekte einer Astrozytenschwellung auf die Zinkhomöostase unter Verwendung verschiedener zinksensitiver Fluoreszenzindikatoren (Newport Green, Zinquin und RhodZin-3-AM) untersucht und zugrundeliegende Mechanismen charakterisiert. Es konnte gezeigt werden, dass eine durch Hypoosmolarität (205 mosmol/L) induzierte Astrozytenschwellung bereits nach 15 Minuten eine anhaltende, aber durch Einstellung von normoosmotischen Bedingungen (305 mosmol/L) wieder reversible Steigerung der intrazellulären Konzentration „freier“ Zinkionen ([Zn2+]i) induziert. Die hypoosmotisch-vermittelte Steigerung von [Zn2+]i war sensitiv gegenüber dem Zn2+-Chelator TPEN, den NMDA-Rezeptor-Antagonisten MK801 und AP5, dem Antioxidans Epigallocatechingallat (EGCG) sowie den Stickoxid-Synthase-Inhibitoren L-NMMA und TRIM. Die Untersuchungen in der vorliegenden Arbeit zeigen, dass eine hypoosmotisch-induzierte Zellschwellung mit einer nukleären Akkumulation der zinksensitiven Transkriptionsfaktoren metallresponsiver Transkriptionsfaktor 1 (MTF-1) und Spezifitätsprotein 1 (SP1) assoziiert ist. Während die Hochregulation von MTF-1 mit einer verstärkten Transkription der Metallothionein-(MT)-1/2 mRNA einhergeht, war die nukleäre Akkumulation von SP1 mit einer Expressionssteigerung der mRNA des peripheren Benzodiazepinrezeptors (PBR) vergesellschaftet. Sowohl die nukleäre Akkumulation von MTF-1 und SP1, wie auch die mRNA-Expressionssteigerung von MT-1/2 und PBR werden durch den Zn2+-Chelator TPEN gehemmt. Auch die für die Pathogenese der HE relevanten Faktoren Ammoniak, Diazepam und das pro-inflammatorische Zytokin TNFα, die ebenfalls eine Astrozytenschwellung und die Bildung von oxidativem/nitrosativem Stress auslösen, bewirkten eine Freisetzung von Zinkionen aus Proteinen und eine Erhöhung der intrazellulären Konzentration freier Zinkionen. Die Daten zeigen, dass eine durch hypoosmotisches Medium vermittelte Astrozytenschwellung über eine gesteigerte Stickstoffmonoxid-Synthese die Freisetzung von Zinkionen aus Proteinen bewirkt und über zinkabhängige Transkriptionsfaktoren die Gentranskription aktiviert. Während die [Zn2+]i-abhängige Expressionssteigerung der MT-1/2 mRNA einer zytotoxischen Wirkung freier Zinkionen entgegenwirken könnte, kann vermutet werden, dass die Expressionssteigerung des PBR assoziiert ist mit einer bei HE beobachteten gesteigerten Neurosteroidsynthese.Summary Astrocyte swelling is observed in different types of brain injury and is an important event in the pathogenesis of hepatic encephalopathy (HE). Astrocyte swelling induces the formation of reactive nitrogen and oxygen species (RNOS). RNOS formation was shown to promote the release of protein-bound zinc ions (Zn2+) in different celltypes. Zinc plays an important role for the function of many proteins such as for binding of transcription factors to zinc finger binding domains on the DNA. Therefore disturbed zinc homeostasis as induced by oxidative/nitrosative stress may modulate gene transcription. In the current dissertation the effects of astrocyte swelling on zinc homeostasis were studied using Zn2+-specific fluorescent indicator dyes (Newport Green, Zinquin and RhodZin-3-AM) and the underlying mechanisms were characterized. The results show that astrocyte swelling as induced by hypoosmolarity (205 mosmol/L) increased the concentration of free intracellular zinc ions ([Zn2+]i) already within 15 minutes and remained elevated for up to 12 h of observation. This effect was reversible, as elevated [Zn2+]i returned to control levels after reconstitution of normoosmolarity (305 mosmol/L). The hypoosmotically-induced [Zn2+]i-increase was sensitive to the Zn2+ chelator TPEN, the NMDA receptor antagonists MK801 and AP5, the antioxidant epigallocatechin gallate (EGCG) and to the nitric oxide synthase inhibitors L-NMMA and TRIM. The present study shows that hypoosmotically-induced astrocyte swelling triggers nuclear accumulation of the transcription factors metal response element-binding transcription factor 1 (MTF-1) and the specifity protein (SP1). This was associated with enhanced transcription of the MTF-1 or SP1 responsive genes metallothionein-(MT)-1/2 and peripheral-type benzodiazepine receptor (PBR), respectively. Both, nuclear accumulation of MTF-1 and SP1 as well as increased mRNA expression of MT-1/2 and PBR were abolished by the Zn2+ chelator TPEN. Also further HE-relevant factors such as ammonia, diazepam and the pro-inflammatory cytokine TNFα elevated [Zn2+]i. The data show that hypoosmotically-induced astrocyte swelling elevates the intracellular concentration of free zinc ions in a nitric oxide dependent way and enhances zinc dependent gene transcription. Whereas the [Zn2+]i-mediated elevation of MT-1/2 mRNA expression may counteract cytotoxic effects of free zinc ions, an elevated expression of PBR may enhance neurosteroid synthesis as observed in brain in HE. | |||||||
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| Rechtliche Vermerke: | Erklärung zum Eigenanteil der Dissertationsschrift
Doktorandin Grünig (geb. Kruczek), Carolin Die Arbeit wurde in der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf unter Betreuung von Univ.-Prof. Dr. med. Dieter Häussinger durchgeführt. Die Konzeption der Studie erfolgte durch Univ.-Prof. Dr. med. Dieter Häussinger, Direktor der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf, und Prof. Dr. rer. nat. Freimut Schliess und Dr. oec. troph. Boris Görg, wissenschaftliche Mitarbeiter des Sonderforschungsbereiches SFB 575 „Experimentelle Hepatologie“ der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf in Zusammenarbeit mit Prof. Dr. rer. nat. Klaus-Dietrich Kröncke aus dem Institut für Biochemie und Molekularbiologie I der Heinrich-Heine-Universität Düsseldorf. Die Versuche wurden allesamt bis auf unten angegebene nach Einarbeitung durch Dr. oec. troph. Boris Görg, wissenschaftlicher Mitarbeiter der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf, und Torsten Janssen, technischer Mitarbeit der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf, von mir eigenständig durchgeführt. Die Präparation der kultivierten Rattenastrozyten erfolgte durch Brigida Ziegler, Mitarbeiterin der Klinik für Neurologie der Heinrich-Heine-Universität Düsseldorf. Die Ratten stammten aus dem Organentnahmeprojekt 036/11, Leiter Prof. Dr. Werner Müller, Neurochemisches Labor der Klinik für Neurologie der Heinrich-Heine-Universität Düsseldorf. Der zytoplasmatische, nukleäre und mitochondriale Zn2+-Nachweis in kultivierten Rattenastrozyten wurde mit Unterstützung von Dr. oec. troph. Boris Görg und Torsten Janssen aus der Klinik für Gastroenterologie der Heinrich-Heine-Universität Düsseldorf durchgeführt. Die dreidimensionale Rekonstruktion der konfokalen Laserscanning-Mikroskopaufnahmen wurde von Herrn Dr. oec. troph. Boris Görg durchgeführt. Die Analysen zur fluoreszenzmikroskopischen Vitalitätsüberprüfung der Astrozyten mittels Propidium Iodid wurden ebenfalls mit Unterstützung von Dr. Boris Görg und Torsten Janssen durchgeführt. Die Analysen zur Realtime-Polymerasekettenreaktion wurden von Frau Prof. Dr. med. Verena Keitel aus der Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf durchgeführt. Die statistische Auswertung erfolgte mit Unterstützung von Dr. oec. troph. Boris Görg. Ich versichere, das Manuskript selbständig verfasst zu haben und keine weiteren als die von mir angegebenen Quellen verwendet zu haben. Ich versichere, dass alle von mir gemachten Angaben wahrheitsgemäß und vollständig sind. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | 2006 - 2019 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 14.08.2019 | |||||||
| Dateien geändert am: | 14.08.2019 | |||||||
| Promotionsantrag am: | 25.10.2018 | |||||||
| Datum der Promotion: | 12.06.2019 |
