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  • 1
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    Online Resource
    Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of the American Society of Nephrology Vol. 29, No. 3 ( 2018-3), p. 880-905
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 3 ( 2018-3), p. 880-905
    Abstract: Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF- β 1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo , EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2017050479
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2029124-3
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  • 2
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    Online Resource
    Metabolic Reprogramming during Microglia Activation
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Immunometabolism Vol. 1, No. 1 ( 2019-06-04)
    Details
    In: Immunometabolism, Ovid Technologies (Wolters Kluwer Health), Vol. 1, No. 1 ( 2019-06-04)
    Abstract: Microglia, the specialized macrophages of the brain, can adopt different shapes and functions, some of which may be detrimental for nervous tissue. Similar to other immune cells, the metabolic program may determine the phenotypic features of microglia, and could constitute a therapeutic target in neurological diseases. Because the knowledge on microglial metabolism was sparse we here employed mouse primary microglia cells polarized into a pro- or anti-inflammatory state to define their metabolic features. After stimulation with either IL1β/IFNγ or IL4, the activity of glycolysis, glucose oxidation, glutamine oxidation, mitochondrial and peroxisomal fatty acid β-oxidation, and fatty acid synthesis, was assessed by using radiolabeled substrates. We complemented these data with transcriptome analysis of key enzymes orchestrating these metabolic pathways. Pro-inflammatory microglia exhibit increased glucose and glutamine metabolism and suppress both fatty acid oxidation and to a lesser extent fatty acid synthesis. On the other hand, anti-inflammatory microglia display changes only in fatty acid metabolism upregulating both fatty acid oxidation and fatty acid synthesis. Importantly, also human microglia-like cells differentiated from pluripotent stem cells upregulate glycolysis in pro-inflammatory conditions. Finally, we show that glycolytic enzymes are induced in a pro-inflammatory brain environment in vivo in mice. Taken together, the distinct metabolism in pro- and anti-inflammatory microglia can constitute a target to direct the microglial phenotype.
    Type of Medium: Online Resource
    ISSN: 2633-0407
    URL: Article
    DOI: 10.20900/immunometab20190002
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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