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  • 1
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    Online Resource
    Deciphering the Contribution of Inflammatory Macrophages to Focal Segmental Glomerulosclerosis : TH-PO548
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 11S ( 2023-11), p. 243-243
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 11S ( 2023-11), p. 243-243
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.20233411S1243c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 2
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    Nephrotisches Syndrom: Überblick und Basis
    Georg Thieme Verlag KG ; 2022
    In:  DMW - Deutsche Medizinische Wochenschrift Vol. 147, No. 06 ( 2022-03), p. 332-336
    Details
    In: DMW - Deutsche Medizinische Wochenschrift, Georg Thieme Verlag KG, Vol. 147, No. 06 ( 2022-03), p. 332-336
    Abstract: Einteilung der Minimal-Change-Disease und fokalen und segmentalen Glomerulosklerose Das zunehmende Wissen über die verschiedenen Auslöser der MCD und FSGS spiegelt sich in den neuen KDIGO-Leitlinien wider, welche eine klare Einteilung der (MCD und) FSGS in primäre, sekundäre und genetische Ursachen vorsieht. Die korrekte Klassifizierung ist wichtig und hat eine direkte Auswirkung auf die Therapie. Therapie Die Therapie besteht bei der primären MCD und FSGS weiterhin aus Steroiden oder – bei Nichtansprechen bzw. Kontraindikationen – aus Calcineurin-Inhibitoren, Mycophenolatmofetil oder Cyclophosphamid. Auch Rituximab findet in refraktären Fällen als „Off-Label“ Verwendung. Bei sekundären Formen wird die Grunderkrankung behandelt. Ausblick Mit Sparsentan befindet sich ein neuer Wirkstoff in der klinischen Testung. Bereits jetzt können SGLT-2-Inhibitoren verschrieben werden, um einen eGFR-Verlust zu minimieren. Die zeitnahe (kinder-)nephrologische Anbindung von Patienten mit MCD/FSGS ist für das Outcome von großer Bedeutung. Durch das nationale FOrMe-Register stehen regionale Experten für die Behandlung der MCD und FSGS zur Verfügung.
    Type of Medium: Online Resource
    ISSN: 0012-0472 , 1439-4413
    URL: Article
    DOI: 10.1055/a-1334-2135
    RVK:
    XA 39100
    RVK:
    XA 10000
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2022
    detail.hit.zdb_id: 2035474-5
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  • 3
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    Generation of CX3CR1-Expressing T Regulatory Cells Using Retroviral Transduction : TH-PO543
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 11S ( 2023-11), p. 242-242
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 11S ( 2023-11), p. 242-242
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.20233411S1242a
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 4
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    Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 8 ( 2023-08), p. 1366-1380
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 8 ( 2023-08), p. 1366-1380
    Abstract: Treatment of acute, crescentic glomerulonephritis (GN) consists of unspecific and potentially toxic immunosuppression. T cells are central in the pathogenesis of GN, and various checkpoint molecules control their activation. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown potential for restraining inflammation in other T-cell–mediated disease models. To investigate its role in GN in a murine model of crescentic nephritis, the authors induced nephrotoxic nephritis in BTLA-deficient mice and wild-type mice. They found that BTLA has a renoprotective role through suppression of local Th1-driven inflammation and expansion of T regulatory cells and that administration of an agonistic anti-BTLA antibody attenuated experimental GN. These findings suggest that antibody-based modulation of BTLA may represent a treatment strategy in human glomerular disease. Background Modulating T-lymphocytes represents a promising targeted therapeutic option for glomerulonephritis (GN) because these cells mediate damage in various experimental and human GN types. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown its potential to restrain inflammation in other T-cell–mediated disease models. Its role in GN, however, has not been investigated. Methods We induced nephrotoxic nephritis (NTN), a mouse model of crescentic GN, in Btla -deficient ( Btla KO ) mice and wild-type littermate controls and assessed disease severity using functional and histologic parameters at different time points after disease induction. Immunologic changes were comprehensively evaluated by flow cytometry, RNA sequencing, and in vitro assays for dendritic cell and T-cell function. Transfer experiments into Rag1 KO mice confirmed the observed in vitro findings. In addition, we evaluated the potential of an agonistic anti-BTLA antibody to treat NTN in vivo . Results The Btla KO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells. Single-cell RNA sequencing showed increased renal T-cell activation and positive regulation of the immune response. Although BTLA-deficient regulatory T cells (Tregs) exhibited preserved suppressive function in vitro and in vivo , Btla KO T effector cells evaded Treg suppression. Administration of an agonistic anti-BTLA antibody robustly attenuated NTN by suppressing nephritogenic T effector cells and promoting Treg expansion. Conclusions In a model of crescentic GN, BTLA signaling effectively restrained nephritogenic Th1 cells and promoted regulatory T cells. Suppression of T-cell–mediated inflammation by BTLA stimulation may prove relevant for a broad range of conditions involving acute GN.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.0000000000000159
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 5
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    Super-Resolution Imaging of the Filtration Barrier Suggests a Role for Podocin R229Q in Genetic Predisposition to Glomerular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of the American Society of Nephrology Vol. 33, No. 1 ( 2022-1), p. 138-154
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 1 ( 2022-1), p. 138-154
    Abstract: Podocin R229Q results from the most frequent missense variant in NPHS2 , and its association with FSGS when podocin R229Q is transassociated with a second mutation in NPHS2 is well recognized. However, because results from observational studies are ambiguous and appropriate animal studies are lacking, its isolated pathogenic potency is not entirely clear. In this study, the authors introduced this genetic alteration in mice and assessed the phenotype using super-resolution microscopy and albuminuria measurements. They demonstrated a deleterious effect of the variant on podocyte morphology and on the integrity of the glomerular filtration barrier under basal conditions and after external glomerular injury. Because this finding suggests that this mutation confers a genetic predisposition to glomerular disease, it has implications for a large number of carriers worldwide. Background Diseases of the kidney’s glomerular filtration barrier are a leading cause of end stage renal failure. Despite a growing understanding of genes involved in glomerular disorders in children, the vast majority of adult patients lack a clear genetic diagnosis. The protein podocin p.R229Q, which results from the most common missense variant in NPHS2 , is enriched in cohorts of patients with FSGS. However, p.R229Q has been proposed to cause disease only when transassociated with specific additional genetic alterations, and population-based epidemiologic studies on its association with albuminuria yielded ambiguous results. Methods To test whether podocin p.R229Q may also predispose to the complex disease pathogenesis in adults, we introduced the exact genetic alteration in mice using CRISPR/Cas9-based genome editing ( PodR231Q ). We assessed the phenotype using super-resolution microscopy and albuminuria measurements and evaluated the stability of the mutant protein in cell culture experiments. Results Heterozygous PodR231Q/wild-type mice did not present any overt kidney disease or proteinuria. However, homozygous PodR231Q/R231Q mice developed increased levels of albuminuria with age, and super-resolution microscopy revealed preceding ultrastructural morphologic alterations that were recently linked to disease predisposition. When injected with nephrotoxic serum to induce glomerular injury, heterozygous PodR231Q/wild-type mice showed a more severe course of disease compared with Podwild-type/wild-type mice. Podocin protein levels were decreased in PodR231Q/wild-type and PodR231Q/R231Q mice as well as in human cultured podocytes expressing the podocin R231Q variant. Our in vitro experiments indicate an underlying increased proteasomal degradation. Conclusions Our findings demonstrate that podocin R231Q exerts a pathogenic effect on its own, supporting the concept of podocin R229Q contributing to genetic predisposition in adult patients.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2020060858
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2029124-3
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  • 6
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    The role of the immune system in idiopathic nephrotic syndrome
    Springer Science and Business Media LLC ; 2021
    In:  Molecular and Cellular Pediatrics Vol. 8, No. 1 ( 2021-12)
    Details
    In: Molecular and Cellular Pediatrics, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2021-12)
    Abstract: Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.
    Type of Medium: Online Resource
    ISSN: 2194-7791
    URL: Article
    DOI: 10.1186/s40348-021-00128-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2785551-X
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  • 7
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    The role of the FSGS disease gene product and nuclear pore protein NUP205 in regulating nuclear localization and activity of transcriptional regulators YAP and TAZ
    Oxford University Press (OUP) ; 2023
    In:  Human Molecular Genetics ( 2023-08-11)
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), ( 2023-08-11)
    Abstract: Mutations in genes encoding nuclear pore proteins (NUPs) lead to the development of steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). However, the precise molecular mechanisms by which NUP dysfunction contributes to podocyte injury preceding FSGS remain unclear. The tightly regulated activity of Yes-associated protein (YAP) and WW-domain-containing transcription regulator 1 (TAZ), the transcriptional effectors of the Hippo pathway, is crucial for podocytes and the maintenance of the glomerular filter. In this study, we investigate the impact of NUPs on the regulation of YAP/TAZ nuclear import and activity in podocytes. In unbiased interactome studies using quantitative label-free mass spectrometry, we identify the FSGS disease gene products NUP107, NUP133, NUP205, and Exportin-5 (XPO5) as components of YAP and TAZ protein complexes in podocytes. Moreover, we demonstrate that NUP205 is essential for YAP/TAZ nuclear import. Consistently, both the nuclear interaction of YAP/TAZ with TEA domain transcription factor 1 and their transcriptional activity were dependent on NUP205 expression. Additionally, we elucidate a regulatory feedback mechanism whereby YAP activity is modulated in response to TAZ-mediated NUP205 expression. In conclusion, this study establishes a connection between the FSGS disease protein NUP205 and the activity of the transcriptional regulators and Hippo effectors YAP and TAZ and it proposes a potential pathological role of YAP/TAZ dysregulation in podocytes of patients with pathogenic NUP205 variants.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddad135
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 8
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    T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Society of Nephrology Vol. 28, No. 1 ( 2017-1), p. 185-196
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 1 ( 2017-1), p. 185-196
    Abstract: Th1 cells are central pathogenic mediators of crescentic GN (cGN). Mechanisms responsible for Th1 cell downregulation, however, remain widely unknown. Recently, it was proposed that activation of the Th1–characteristic transcription factor T-bet optimizes Foxp3 + regulatory T (Treg) cells to counteract Th1-type inflammation. Because very little is known about the role of T-bet + Treg1 cells in inflammatory diseases, we studied the function of these cells in the nephrotoxic nephritis (NTN) model of cGN. The percentage of Treg1 cells progressively increased in kidneys of nephritic wild–type mice during the course of NTN, indicating their functional importance. Notably, naïve Foxp3 Cre xT-bet fl/fl mice, lacking Treg1 cells, showed spontaneous skewing toward Th1 immunity. Furthermore, absence of Treg1 cells resulted in aggravated NTN with selectively dysregulated renal and systemic Th1 responses. Detailed analyses of Treg cells from Foxp3 Cre xT-bet fl/fl mice revealed unaltered cytokine production and suppressive capacity. However, in competitive cotransfer experiments, wild–type Treg cells outcompeted T-bet–deficient Treg cells in terms of population expansion and expression levels of Foxp3, indicating that T-bet expression is crucial for general Treg fitness. Additionally, T-bet–deficient Treg cells lacked expression of the Th1–characteristic trafficking receptor CXCR3, which correlated with significant impairment of renal Treg infiltration. In summary, our data indicate a new subtype of Treg cells in cGN. These Treg1 cells are characterized by activation of the transcription factor T-bet, which enhances the overall fitness of these cells and optimizes their capacity to downregulate Th1 responses by inducing chemokine receptor CXCR3 expression.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2015070820
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2029124-3
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  • 9
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    Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer
    Elsevier BV ; 2022
    In:  Cancer Cell Vol. 40, No. 2 ( 2022-02), p. 168-184.e13
    Details
    In: Cancer Cell, Elsevier BV, Vol. 40, No. 2 ( 2022-02), p. 168-184.e13
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2022.01.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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  • 10
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    IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of the American Society of Nephrology Vol. 29, No. 7 ( 2018-7), p. 1825-1837
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 7 ( 2018-7), p. 1825-1837
    Abstract: Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear. Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed. Results Compared with controls, mice with IL-10Ra −/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6 + Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra −/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra −/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra −/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN. Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2017091044
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2029124-3
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