Dokument: Die Funktionen von GLEPP1 im Podozyten und dessen Bedeutung für die Integrität der glomerulären Schlitzmembran

Titel:

Die Funktionen von GLEPP1 im Podozyten und dessen Bedeutung für die Integrität der glomerulären Schlitzmembran

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=49432

URN (NBN):

urn:nbn:de:hbz:061-20190429-110016-2

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Grabowski, Sarah [Autor]

Dateien:

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Dateien vom 23.04.2019 / geändert 23.04.2019

Beitragende:

Prof. Dr. med. Sellin, Lorenz [Gutachter]
Prof. Dr. MacKenzie, Colin [Gutachter]

Stichwörter:

GLEPP1

Dewey Dezimal-Klassifikation:

600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit

Beschreibungen:

Proteinurische Nierenerkrankungen stellen seit Jahren eine zunehmende Herausforderung für die Medizin und die Gesundheitssysteme dar. Vergangene Studien zeigten, dass bei einigen proteinurischen Nierenerkrankungen die Expression von GLEPP1 stark herab gesetzt ist [1, 2]. GLEPP1 ist eine Rezeptor-Protein-Tyrosin-Phosphatase (RPTP), die sich am apikalen Pol des podozytären Fußfortsatzes befindet. Mäuse mit fehlerhafter Bildung von GLEPP1 zeigten unter Belastung und beim Altern eine renale Symptomatik [3].
Ziel der durchgeführten Experimente war es, die physiologische Funktion von GLEPP1 im Podozyten zu erforschen und die Bedeutung von GLEPP1 für die Integrität der glomerulären Schlitzmembran genauer zu untersuchen.
Dazu wurden Human Embryonale Kidney 293 T Zellen (HEK 293 T Zellen) in der Zellkultur mit GLEPP1 und den zu untersuchenden möglichen Interaktionspartner von GLEPP1 (z.B. verschiedene Src- Kinasen) transfiziert. Die Zellen wurden am nächsten Tag lysiert. Um eine Interaktion der über Nacht exprimierten Proteine nachzuweisen, wurde eine Co-Immunopräzipitation durchgeführt.
Es wurde gezeigt, dass GLEPP1 sowohl mit Nephrin, als auch Podocin, sowie mit den Src-Familien-Kinasen Fyn und Src interagiert. Des Weiteren zeigte sich, dass GLEPP1 Src und Fyn am Tyrosin 527 dephosphoryliert und somit aktiviert. Die Nephrin-Podocin-Interaktion wurde durch GLEPP1 verstärkt und die Nephrin-ß-arrestin2-Interaktion wurde durch GLEPP1 geschwächt. Abschließend wurde gezeigt, dass GLEPP1 die Endozytose von Nephrin reduziert.
Wir konnten mit dieser Studie dazu beitragen wichtige neue Erkenntnisse über die RPTP GLEPP1 zu gewinnen. Die Ergebnisse unserer Versuche passen zu der Theorie, dass GLEPP1 über seine Phosphatase-Aktivität SFK dephosphoryliert und somit aktiviert. Die SFKs können Nephrin vermehrt phosphorylieren und Podocin bindet und stabilisiert daraufhin Nephrin in der Schlitzmembran. Die Endozytose von Nephrin wird somit von GLEPP1 verringert. Die Bestätigung dieser Theorie durch unsere Ergebnisse hilft uns, ein genaueres Bild über die Funktionen und Aufgaben von GLEPP1 im Podozyten zu zeichnen. Es wird immer deutlicher, dass die Phosphatase-Aktivität von GLEPP1 essentiell an der physiologi-schen Regulation und Funktion des glomerulären Filters beteiligt ist. Deshalb gilt es die ge-wonnenen Ergebnisse dieser Arbeit durch weiterführende in vivo Versuche zu bestätigen und das beschriebene Bild von GLEPP1 zu vervollständigen.

Proteinuric kidney diseases have been an increasing challange for medical therapies and health care systems for years. Past studies have shown that in some proteinuric kidney dis-eases the expression of GLEPP1 is strongly reduced [1, 2]. GLEPP1 is a receptor protein tyrosine phosphatase (RPTP) located at the apical pole of the podocyte foot processes. Mice with lack of GLEPP1 expression showed renal symptoms if challenged or at advanced age [3].
The experiments in this study aimed to discover the molecular physiological functions of GLEPP1 in the podocyte and to investigate the further role of GLEPP1 for the integrity of the glomerular slit diaphragm.
Therefore, human embryonal kidney 293 T cells (HEK 293 T cells) were transfected with GLEPP1 and the potential interaction partners of GLEPP1 (i.e. Src kinases). The cells were lysed the following day, followed by a co-immunoprecipitation was to detect the interacting proteins.
We were able to show that GLEPP1 interacts with both nephrin and podocin, as well as with the Src family kinases (SFK) Fyn and Src. Furthermore, we demonstrated that GLEPP1 dephosphorylates and thus activates Src and Fyn at tyrosine 527. Nephrin-podocin-interaction was increased by GLEPP1 and the nephrin-ß-arrestin2-interaction was decreased by GLEPP1. Finally, as a result of the increased interaction with ß-arrestin2, GLEPP1 reduces the endocytosis of nephrin.
With this study, we contributed to new discoveries about the molecular function of the RPTP GLEPP1. The results of our experiments fit the theory that GLEPP1 dephosphorylates and thus activates SFKs through its phosphatase activity. The activated SFKs can therefore in-crease the phosphorylation of nephrin. Podocin binds to phosphorylated nephrin and stabilizes nephrin in the slit diaphragm. Thus, the endocytosis of nephrin is decreased by GLEPP1. By confirming this theory with our results, we gained better understanding of GLEPP1 functions in the podocyte. It is increasingly clear that the phosphatase activity of GLEPP1 is an essential part of the physiological regulation and function of the glomerular filter. Hopefully the results of this study will be confirmed and expanded through further in vivo experiments so we can reach a complete and detailed understanding of GLEPP1 in vivo.

Quelle:

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3. Wang, R., et al., Molecular cloning, expression, and distribution of glomerular epithelial protein 1 in developing mouse kidney. Kidney Int, 2000. 57(5): p. 1847-59.
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5. Hallan, S.I., et al., International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol, 2006. 17(8): p. 2275-84.
6. Wen, C.P., et al., All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet, 2008. 371(9631): p. 2173-82.
7. Chadban, S.J., et al., Prevalence of kidney damage in Australian adults: The AusDiab kidney study. J Am Soc Nephrol, 2003. 14(7 Suppl 2): p. S131-8.
8. Lysaght, M.J., Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol, 2002. 13 Suppl 1: p. S37-40.
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17. Kees-Folts, D., J.L. Sadow, and G.F. Schreiner, Tubular catabolism of albumin is associated with the release of an inflammatory lipid. Kidney Int, 1994. 45(6): p. 1697-709.
18. Donadelli, R., et al., Protein overload induces fractalkine upregulation in proximal tubular cells through nuclear factor kappaB- and p38 mitogen-activated protein kinase-dependent pathways. J Am Soc Nephrol, 2003. 14(10): p. 2436-46.
19. Bakoush, O., et al., High proteinuria selectivity index based upon IgM is a strong predictor of poor renal survival in glomerular diseases. Nephrol Dial Transplant, 2001. 16(7): p. 1357-63.
20. Sandsmark, D.K., et al., Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease: Chronic Renal Insufficiency Cohort Study. Stroke, 2015. 46(8): p. 2075-80.
21. Tryggvason, K., J. Patrakka, and J. Wartiovaara, Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med, 2006. 354(13): p. 1387-401.
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26. Hudson, B.G., et al., Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med, 2003. 348(25): p. 2543-56.
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28. Noakes, P.G., et al., The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat Genet, 1995. 10(4): p. 400-6.
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Urheberrechtsschutz

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Düsseldorf 2009-2019

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29.04.2019

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30.07.2018

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11.04.2019

Heinrich-Heine-Universität Düsseldorf

Dokument: Die Funktionen von GLEPP1 im Podozyten und dessen Bedeutung für die Integrität der glomerulären Schlitzmembran