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  1. Article ; Online: Kif21a deficiency leads to impaired glomerular filtration barrier function

    Hanna Riedmann / Séverine Kayser / Martin Helmstädter / Daniel Epting / Carsten Bergmann

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract The renal glomerulus represents the major filtration body of the vertebrate nephron and is responsible for urine production and a number of other functions such as metabolic waste elimination and the regulation of water, electrolyte and acid– ... ...

    Abstract Abstract The renal glomerulus represents the major filtration body of the vertebrate nephron and is responsible for urine production and a number of other functions such as metabolic waste elimination and the regulation of water, electrolyte and acid–base balance. Podocytes are highly specialized epithelial cells that form a crucial part of the glomerular filtration barrier (GFB) by establishing a slit diaphragm for semipermeable plasma ultrafiltration. Defects of the GFB lead to proteinuria and impaired kidney function often resulting in end-stage renal failure. Although significant knowledge has been acquired in recent years, many aspects in podocyte biology are still incompletely understood. By using zebrafish as a vertebrate in vivo model, we report a novel role of the Kinesin-like motor protein Kif21a in glomerular filtration. Our studies demonstrate specific Kif21a localization to the podocytes. Its deficiency resulted in altered podocyte morphology leading to podocyte foot process effacement and altered slit diaphragm formation. Finally, we proved considerable functional consequences of Kif21a deficiency by demonstrating a leaky GFB resulting in severe proteinuria. Conclusively, our data identified a novel role of Kif21a for proper GFB function and adds another piece to the understanding of podocyte architecture and regulation.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes

    Dominik Spitz / Maria Comas / Lea Gerstner / Séverine Kayser / Martin Helmstädter / Gerd Walz / Tobias Hermle

    Cells, Vol 11, Iss 2103, p

    2022  Volume 2103

    Abstract: Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains ... ...

    Abstract Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms. Gain-of-function of mTOR signaling did not affect spacing, suggesting that additional cues limit the maximal slit diaphragm density. Interestingly, both activation and inhibition of mTOR signaling led to decreased nephrocyte function, indicating that a fine balance of signaling activity is needed for proper function. Furthermore, mTOR positively controlled cell size, survival, and the extent of the subcortical actin network. We also showed that basal autophagy in nephrocytes is required for survival and limits the expression of the sns (nephrin) but does not directly affect slit diaphragm formation or endocytic activity. However, using a genetic rescue approach, we demonstrated that excessive, mTOR-dependent autophagy is primarily responsible for slit diaphragm misspacing. In conclusion, we established this invertebrate podocyte model for mechanistic studies on the role of mTOR signaling and autophagy, and we discovered a direct mTOR/autophagy-dependent regulation of the slit diaphragm architecture.
    Keywords nephrocyte ; Drosophila ; podocyte ; mTOR ; autophagy ; slit diaphragm ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Selective endocytosis controls slit diaphragm maintenance and dynamics in Drosophila nephrocytes

    Konrad Lang / Julian Milosavljevic / Helena Heinkele / Mengmeng Chen / Lea Gerstner / Dominik Spitz / Severine Kayser / Martin Helmstädter / Gerd Walz / Michael Köttgen / Andrew Spracklen / John Poulton / Tobias Hermle

    eLife, Vol

    2022  Volume 11

    Abstract: The kidneys generate about 180 l of primary urine per day by filtration of plasma. An essential part of the filtration barrier is the slit diaphragm, a multiprotein complex containing nephrin as major component. Filter dysfunction typically manifests ... ...

    Abstract The kidneys generate about 180 l of primary urine per day by filtration of plasma. An essential part of the filtration barrier is the slit diaphragm, a multiprotein complex containing nephrin as major component. Filter dysfunction typically manifests with proteinuria and mutations in endocytosis regulating genes were discovered as causes of proteinuria. However, it is unclear how endocytosis regulates the slit diaphragm and how the filtration barrier is maintained without either protein leakage or filter clogging. Here, we study nephrin dynamics in podocyte-like nephrocytes of Drosophila and show that selective endocytosis either by dynamin- or flotillin-mediated pathways regulates a stable yet highly dynamic architecture. Short-term manipulation of endocytic functions indicates that dynamin-mediated endocytosis of ectopic nephrin restricts slit diaphragm formation spatially while flotillin-mediated turnover of nephrin within the slit diaphragm is needed to maintain filter permeability by shedding of molecules bound to nephrin in endosomes. Since slit diaphragms cannot be studied in vitro and are poorly accessible in mouse models, this is the first analysis of their dynamics within the slit diaphragm multiprotein complex. Identification of the mechanisms of slit diaphragm maintenance will help to develop novel therapies for proteinuric renal diseases that are frequently limited to symptomatic treatment.
    Keywords nephrocyte ; podocyte ; endocytosis ; nephrin ; proteinuria ; Drosophila ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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