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  • 1
    Online Resource
    Online Resource
    Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling
    The Company of Biologists ; 2022
    In:  Development Vol. 149, No. 9 ( 2022-05-01)
    Details
    In: Development, The Company of Biologists, Vol. 149, No. 9 ( 2022-05-01)
    Abstract: Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.
    Type of Medium: Online Resource
    ISSN: 0950-1991 , 1477-9129
    URL: Article
    DOI: 10.1242/dev.200198
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2022
    detail.hit.zdb_id: 2007916-3
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte
    Wiley ; 2015
    In:  The Journal of Pathology Vol. 237, No. 4 ( 2015-12), p. 472-481
    Details
    In: The Journal of Pathology, Wiley, Vol. 237, No. 4 ( 2015-12), p. 472-481
    Abstract: The glomerular filtration barrier consists of podocytes, the glomerular basement membrane, and endothelial cells covered with a glycocalyx. Heparan sulphate ( HS ) in the glomerular filtration barrier is reduced in patients with proteinuria, which is associated with increased expression of the HS ‐degrading enzyme heparanase. Previously, we showed that heparanase is essential for the development of proteinuria in experimental diabetic nephropathy. Vitamin D supplementation reduces podocyte loss and proteinuria in vitro and in vivo . Therefore, we hypothesize that vitamin D reduces proteinuria by reducing glomerular heparanase. Adriamycin‐exposed rats developed proteinuria and showed increased heparanase expression, which was reduced by 1,25‐dihydroxyvitamin D 3 (1,25‐ D 3 ) treatment. In vitro , adriamycin increased heparanase mRNA in the podocyte, which could be corrected by 1,25‐ D 3 treatment. In addition, 1,25‐ D 3 treatment reduced transendothelial albumin passage after adriamycin stimulation. In line with these results, we showed direct binding of the vitamin D receptor to the heparanase promoter, and 1,25‐ D 3 dose‐dependently reduced heparanase promoter activity. Finally, 1,25‐ D 3 ‐deficient 25‐hydroxy‐1α‐hydroxylase knockout mice developed proteinuria and showed increased heparanase, which was normalized by 1,25‐ D 3 treatment. Our data suggest that the protective effect of vitamin D on the development of proteinuria is mediated by inhibiting heparanase expression in the podocyte. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2015.237.issue-4
    DOI: 10.1002/path.4593
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1475280-3
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  • 3
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    Primary Focal Segmental Glomerulosclerosis Plasmas Increase Lipid Droplet Formation and Perilipin-2 Expression in Human Podocytes
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 24, No. 1 ( 2022-12-22), p. 194-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 1 ( 2022-12-22), p. 194-
    Abstract: Many patients with primary focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation. Several circulating permeability factors (CPFs) responsible for recurrence have been suggested, but were never validated. We aimed to find proteins involved in the mechanism of action of CPF(s) and/or potential biomarkers for the presence of CPF(s). Cultured human podocytes were exposed to plasma from patients with FSGS with presumed CPF(s) or healthy and disease controls. Podocyte proteomes were analyzed by LC–MS. Results were validated using flow cytometry, RT-PCR, and immunofluorescence. Podocyte granularity was examined using flow cytometry, electron microscopy imaging, and BODIPY staining. Perilipin-2 protein expression was increased in podocytes exposed to presumed CPF-containing plasmas, and correlated with the capacity of plasma to induce podocyte granularity, identified as lipid droplet accumulation. Elevated podocyte perilipin-2 was confirmed at protein and mRNA level and was also detected in glomeruli of FSGS patients whose active disease plasmas induced podocyte perilipin-2 and lipid droplets. Our study demonstrates that presumably, CPF-containing plasmas from FSGS patients induce podocyte lipid droplet accumulation and perilipin-2 expression, identifying perilipin-2 as a potential biomarker. Future research should address the mechanism underlying CPF-induced alterations in podocyte lipid metabolism, which ultimately may result in novel leads for treatment.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24010194
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Hepatocyte Nuclear Factor 1β–Associated Kidney Disease : More than Renal Cysts and Diabetes
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of the American Society of Nephrology Vol. 27, No. 2 ( 2016-02), p. 345-353
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 27, No. 2 ( 2016-02), p. 345-353
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.2015050544
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2029124-3
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  • 5
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    Online Resource
    Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of the American Society of Nephrology Vol. 33, No. 2 ( 2022-02), p. 305-325
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 2 ( 2022-02), p. 305-325
    Abstract: Biallelic pathogenic variants in SLC12A3 , encoding the thiazide-sensitive sodium chloride cotransporter NCC, cause Gitelman syndrome. Gitelman patients suffer from hypokalemic alkalosis, hypomagnesemia, and salt wasting. A subset of Gitelman syndrome cases remains genetically unsolved. This paper describes the identification of pathogenic mitochondrial DNA (mtDNA) variants in the genes encoding the transfer RNAs for phenylalanine ( MT-TF ) and isoleucine ( MT-TI ) in 13 families with a Gitelman-like phenotype. Six families were additionally affected by progressive CKD. Mitochondrial dysfunction was demonstrated in patient-derived fibroblasts and linked to defective sodium reabsorption by NCC in vitro. These findings advocate for screening for mtDNA variants in unexplained Gitelman syndrome patients and influence genetic counseling of affected families. Furthermore, they provide insight into the physiology of renal sodium handling. Background Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na + -Cl − cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB , HNF1B , FXYD2 , or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. Methods We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF , which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22 Na + transport. Results Genetic investigations revealed four mtDNA variants in 13 families: m.591C 〉 T ( n =7), m.616T 〉 C ( n =1), m.643A 〉 G ( n =1) (all in MT-TF ), and m.4291T 〉 C ( n =4, in MT-TI ). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A 〉 G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2021050596
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2029124-3
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  • 6
    Online Resource
    Online Resource
    Acid-Base Status Determines the Renal Expression of Ca2+ and Mg2+ Transport Proteins
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Journal of the American Society of Nephrology Vol. 17, No. 3 ( 2006-03), p. 617-626
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 3 ( 2006-03), p. 617-626
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.2005070732
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
    detail.hit.zdb_id: 2029124-3
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  • 7
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    1,25-Vitamin D3 Deficiency Induces Albuminuria
    Elsevier BV ; 2016
    In:  The American Journal of Pathology Vol. 186, No. 4 ( 2016-04), p. 794-804
    Details
    In: The American Journal of Pathology, Elsevier BV, Vol. 186, No. 4 ( 2016-04), p. 794-804
    Type of Medium: Online Resource
    ISSN: 0002-9440
    URL: Article
    DOI: 10.1016/j.ajpath.2015.11.015
    RVK:
    XA 10000
    RVK:
    XA 19800
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 1480207-7
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  • 8
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    Laminar flow substantially affects the morphology and functional phenotype of glomerular endothelial cells
    Public Library of Science (PLoS) ; 2021
    In:  PLOS ONE Vol. 16, No. 5 ( 2021-5-5), p. e0251129-
    Details
    In: PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 5 ( 2021-5-5), p. e0251129-
    Abstract: Shear stress induced by laminar blood flow has a profound effect on the morphology and functional phenotype of macrovascular endothelial cells. The influence of laminar flow on the glomerular microvascular endothelium, however, remains largely elusive. The glomerular endothelium, including its glycocalyx, is a crucial part of the glomerular filtration barrier, which is involved in blood filtration. We therefore investigated the influence of laminar flow-induced shear stress on the glomerular endothelium. Conditionally immortalized mouse glomerular endothelial cells were cultured for 7 days under a laminar flow of 5 dyn/cm 2 to mimic the glomerular blood flow. The cells were subsequently analysed for changes in morphology, expression of shear stress-responsive genes, nitric oxide production, glycocalyx composition, expression of anti-oxidant genes and the inflammatory response. Culture under laminar flow resulted in cytoskeletal rearrangement and cell alignment compared to static conditions. Moreover, production of nitric oxide was increased and the expression of the main functional component of the glycocalyx, Heparan Sulfate, was enhanced in response to shear stress. Furthermore, glomerular endothelial cells demonstrated a quiescent phenotype under flow, characterized by a decreased expression of the pro-inflammatory gene ICAM-1 and increased expression of the anti-oxidant enzymes HO-1 and NQO1. Upon exposure to the inflammatory stimulus TNFα, however, glomerular endothelial cells cultured under laminar flow showed an enhanced inflammatory response. In conclusion, laminar flow extensively affects the morphology and functional phenotype of glomerular endothelial cells in culture. Furthermore, glomerular endothelial cells respond differently to shear stress compared to macrovascular endothelium. To improve the translation of future in vitro studies with glomerular endothelial cells to the in vivo situation, it appears therefore crucial to culture glomerular endothelial cells under physiological flow conditions.
    Type of Medium: Online Resource
    ISSN: 1932-6203
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1371/journal.pone.0251129
    DOI: 10.1371/journal.pone.0251129.g001
    DOI: 10.1371/journal.pone.0251129.g002
    DOI: 10.1371/journal.pone.0251129.g003
    DOI: 10.1371/journal.pone.0251129.g004
    DOI: 10.1371/journal.pone.0251129.t001
    DOI: 10.1371/journal.pone.0251129.r001
    DOI: 10.1371/journal.pone.0251129.r002
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2021
    detail.hit.zdb_id: 2267670-3
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  • 9
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    The Efficacy and Safety of (Neo)Adjuvant Therapy for Gastric Cancer: A Network Meta-analysis
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 1 ( 2019-01-11), p. 80-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 1 ( 2019-01-11), p. 80-
    Abstract: Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38–0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58–1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28–0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11010080
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 10
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    Co-Culture of Glomerular Endothelial Cells and Podocytes in a Custom-Designed Glomerulus-on-a-Chip Model Improves the Filtration Barrier Integrity and Affects the Glomerular Cell Phenotype
    MDPI AG ; 2023
    In:  Biosensors Vol. 13, No. 3 ( 2023-03-03), p. 339-
    Details
    In: Biosensors, MDPI AG, Vol. 13, No. 3 ( 2023-03-03), p. 339-
    Abstract: Crosstalk between glomerular endothelial cells and glomerular epithelial cells (podocytes) is increasingly becoming apparent as a crucial mechanism to maintain the integrity of the glomerular filtration barrier. However, in vitro studies directly investigating the effect of this crosstalk on the glomerular filtration barrier are scarce because of the lack of suitable experimental models. Therefore, we developed a custom-made glomerulus-on-a-chip model recapitulating the glomerular filtration barrier, in which we investigated the effects of co-culture of glomerular endothelial cells and podocytes on filtration barrier function and the phenotype of these respective cell types. The custom-made glomerulus-on-a-chip model was designed using soft lithography. The chip consisted of two parallel microfluidic channels separated by a semi-permeable polycarbonate membrane. The glycocalyx was visualized by wheat germ agglutinin staining and the barrier integrity of the glomerulus-on-a-chip model was determined by measuring the transport rate of fluorescently labelled dextran from the top to the bottom channel. The effect of crosstalk on the transcriptome of glomerular endothelial cells and podocytes was investigated via RNA-sequencing. Glomerular endothelial cells and podocytes were successfully cultured on opposite sides of the membrane in our glomerulus-on-a-chip model using a polydopamine and collagen A double coating. Barrier integrity of the chip model was significantly improved when glomerular endothelial cells were co-cultured with podocytes compared to monocultures of either glomerular endothelial cells or podocytes. Co-culture enlarged the surface area of podocyte foot processes and increased the thickness of the glycocalyx. RNA-sequencing analysis revealed the regulation of cellular pathways involved in cellular differentiation and cellular adhesion as a result of the interaction between glomerular endothelial cells and podocytes. We present a novel custom-made glomerulus-on-a-chip co-culture model and demonstrated for the first time using a glomerulus-on-a-chip model that co-culture affects the morphology and transcriptional phenotype of glomerular endothelial cells and podocytes. Moreover, we showed that co-culture improves barrier function as a relevant functional readout for clinical translation. This model can be used in future studies to investigate specific glomerular paracrine pathways and unravel the role of glomerular crosstalk in glomerular (patho) physiology.
    Type of Medium: Online Resource
    ISSN: 2079-6374
    URL: Article
    DOI: 10.3390/bios13030339
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662125-3
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