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  1. Article ; Online: Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy.

    Duret, Lou C / Hamidouche, Tynhinane / Steers, Nicholas J / Pons, Catherine / Soubeiran, Nicolas / Buret, Delphine / Gilson, Eric / Gharavi, Ali G / D'Agati, Vivette D / Shkreli, Marina

    Kidney international

    2024  Volume 105, Issue 5, Page(s) 980–996

    Abstract: Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step ... ...

    Abstract Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
    MeSH term(s) Adult ; Humans ; Mice ; Animals ; Glomerulosclerosis, Focal Segmental/pathology ; Telomerase/therapeutic use ; AIDS-Associated Nephropathy/pathology ; Proteinuria ; Renal Insufficiency/complications ; Disease Models, Animal
    Chemical Substances Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2024-02-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2024.02.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Telomerase is required for glomerular renewal in kidneys of adult mice.

    Montandon, Margo / Hamidouche, Tynhinane / Yart, Lucile / Duret, Lou C / Pons, Catherine / Soubeiran, Nicolas / Pousse, Mélanie / Cervera, Ludovic / Vial, Valérie / Fassy, Julien / Croce, Olivier / Gilson, Eric / Shkreli, Marina

    NPJ Regenerative medicine

    2022  Volume 7, Issue 1, Page(s) 15

    Abstract: Homeostatic renal filtration relies on the integrity of podocytes, which function in glomerular filtration. These highly specialized cells are damaged in 90% of chronic kidney disease, representing the leading cause of end-stage renal failure. Although ... ...

    Abstract Homeostatic renal filtration relies on the integrity of podocytes, which function in glomerular filtration. These highly specialized cells are damaged in 90% of chronic kidney disease, representing the leading cause of end-stage renal failure. Although modest podocyte renewal has been documented in adult mice, the mechanisms regulating this process remain largely unknown and controversial. Using a mouse model of Adriamycin-induced nephropathy, we find that the recovery of filtration function requires up-regulation of the endogenous telomerase component TERT. Previous work has shown that transient overexpression of catalytically inactive TERT (i-TERT
    Language English
    Publishing date 2022-02-11
    Publishing country United States
    Document type Journal Article
    ISSN 2057-3995
    ISSN (online) 2057-3995
    DOI 10.1038/s41536-022-00212-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney.

    Cougnon, Marc / Carcy, Romain / Melis, Nicolas / Rubera, Isabelle / Duranton, Christophe / Dumas, Karine / Tanti, Jean-François / Pons, Catherine / Soubeiran, Nicolas / Shkreli, Marina / Hauet, Thierry / Pellerin, Luc / Giraud, Sébastien / Blondeau, Nicolas / Tauc, Michel / Pisani, Didier F

    Cell death & disease

    2021  Volume 12, Issue 4, Page(s) 283

    Abstract: Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from ... ...

    Abstract Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.
    MeSH term(s) Animals ; Glucose/metabolism ; Kidney/metabolism ; Male ; Mice ; Peptide Initiation Factors/metabolism ; RNA-Binding Proteins/metabolism ; Eukaryotic Translation Initiation Factor 5A
    Chemical Substances Peptide Initiation Factors ; RNA-Binding Proteins ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-03-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-03577-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF2.

    Cherfils-Vicini, Julien / Iltis, Charlene / Cervera, Ludovic / Pisano, Sabrina / Croce, Olivier / Sadouni, Nori / Győrffy, Balázs / Collet, Romy / Renault, Valérie M / Rey-Millet, Martin / Leonetti, Carlo / Zizza, Pasquale / Allain, Fabrice / Ghiringhelli, Francois / Soubeiran, Nicolas / Shkreli, Marina / Vivier, Eric / Biroccio, Annamaria / Gilson, Eric

    The EMBO journal

    2019  Volume 38, Issue 11

    Abstract: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a ... ...

    Abstract Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.
    MeSH term(s) Animals ; Cells, Cultured ; Female ; Gene Expression Regulation, Neoplastic ; Glycocalyx/genetics ; Glycocalyx/metabolism ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Myeloid-Derived Suppressor Cells/metabolism ; Myeloid-Derived Suppressor Cells/physiology ; NIH 3T3 Cells ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/mortality ; Neoplasms/pathology ; Telomere/metabolism ; Telomeric Repeat Binding Protein 2/genetics ; Telomeric Repeat Binding Protein 2/physiology ; Tumor Escape/genetics ; Tumor Escape/physiology
    Chemical Substances TERF2 protein, human ; Telomeric Repeat Binding Protein 2
    Language English
    Publishing date 2019-04-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2018100012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1808: Show issues Location:
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    Zs.MG 100: Show issues

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