Untersuchung des Einflusses von Filaminen auf das Aktin-Zytoskelett und die Adhäsivität mechanisch gedehnter Podozyten

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Titel: Untersuchung des Einflusses von Filaminen auf das Aktin-Zytoskelett und die Adhäsivität mechanisch gedehnter Podozyten

Beteiligte: Greiten, Jonas Konstantin [VerfasserIn]; Endlich, Nicole [AkademischeR BetreuerIn]; Weide, Thomas [AkademischeR BetreuerIn]

Körperschaft: Universität Greifswald

Erschienen: Greifswald, 2022

Umfang: 1 Online-Ressource (PDF-Datei: 79 Seiten, 26862 Kilobyte); Illustrationen (teilweise farbig), Diagramme (teilweise farbig)

Sprache: Deutsch; Englisch

Identifikator:

Schlagwörter: Filamin > Zellskelett > Adhäsion > Podocyte > Niere > Nierenkrankheit > Nephrologie > Diabetes > Hypertonie

Entstehung:

Hochschulschrift: Dissertation, Universitätsmedizin der Universität Greifswald, 2023

Anmerkungen: Literaturverzeichnis: Seite 31-40. - Literaturangaben
Text deutsch, Publikation englisch

Beschreibung: Mechanische Dehnung, Podozyt

Prevalence of chronic kidney disease (CKD) has been steadily increasing globally and especially in industrialized nations lately. The most common causes of CKD are arterial hypertension and diabetes mellitus. These diseases, like glomerular hypertension, are thought to damage the highly specialized and postmitotic podocytes in the kidney. The interdigitating foot processes of podocytes are highly crucial for proper blood filtration and the size selectivity of the kidney filtration barrier. Podocyte foot morphology depends mainly on an intact actin cytoskeleton. Mechanical stress, like glomerular hypertension, may lead to a widening and flattening of these tiny foot processes, which is called effacement. To some extent, podocytes detach from the glomerular basement membrane and are lost forever. In our cultured murine podocytes we observed that the cells respond to mechanical stretch by a complete reorganization of their actin cytoskeleton The question of which mechanosensor or mechanotransducer could be responsible for this is still unknown. Filamins are known to form stable actin networks and could function as mechanosensors. In knockdown and knockout cultured podocytes, we could show that filamin A plays an important role for the F-actin organization. Additionally, we found out that synaptopodin, an important actin-binding protein expressed mainly in podocytes, depends on the filamin A expression and directly interacts with filamin A. After the downregulation and knockout of filamin A, respectively, we observed a downregulation of focal adhesion proteins and integrins. However, we have found that the loss of one isoform did not result in detachment of podocytes during mechanical stress due to compensatory mechanisms between filamin isoforms. Based on these results, we also hypothesized increased expression of filamin A in podocytes under mechanical stress in vivo. Indeed, podocytes in a mouse model of glomerular hypertension and in glomeruli from patients with diabetic nephropathy expressed increased filamin A in podocyte foot processes. Furthermore, we identified filamin A as a new interaction partner of synaptopodin, a podocytespecific actin-binding protein. In summary, these results show the crucial function of filamin A for actin-organization and adhesion of mechanically stretched podocytes. Probably, filamin A may also serve as a mechanosensor which needs to be clarified in further experiments.

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