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Article ; Online: A Putative Role for TRPC6 in Immune-Mediated Kidney Injury.

't Hart, Daan C / van der Vlag, Johan / Nijenhuis, Tom

International journal of molecular sciences

2023 Volume 24, Issue 22

Abstract: Excessive activation of the immune system is the cause of a wide variety of renal diseases. However, the pathogenic mechanisms underlying the aberrant activation of the immune system in the kidneys often remain unknown. TRPC6, a member of the ... ...

Abstract	Excessive activation of the immune system is the cause of a wide variety of renal diseases. However, the pathogenic mechanisms underlying the aberrant activation of the immune system in the kidneys often remain unknown. TRPC6, a member of the Ca
MeSH term(s)	Humans ; TRPC6 Cation Channel/genetics ; TRPC Cation Channels/genetics ; Kidney/pathology ; Kidney Diseases/genetics ; Kidney Diseases/pathology ; Kidney Glomerulus/pathology ; Podocytes/pathology
Chemical Substances	TRPC6 Cation Channel ; TRPC Cation Channels ; TRPC6 protein, human
Language	English
Publishing date	2023-11-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242216419
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Article ; Online: Minimal Change Disease: More Than a Podocytopathy?

Maas, Rutger J / Nijenhuis, Tom / van der Vlag, Johan

Kidney international reports

2022 Volume 7, Issue 4, Page(s) 675–677

Language	English
Publishing date	2022-03-03
Publishing country	United States
Document type	Editorial
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2022.03.001
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Article: Heparanase in Kidney Disease.

van der Vlag, Johan / Buijsers, Baranca

Advances in experimental medicine and biology

2020 Volume 1221, Page(s) 647–667

Abstract: The primary filtration of blood occurs in the glomerulus in the kidney. Destruction of any of the layers of the glomerular filtration barrier might result in proteinuric disease. The glomerular endothelial cells and especially its covering layer, the ... ...

Abstract	The primary filtration of blood occurs in the glomerulus in the kidney. Destruction of any of the layers of the glomerular filtration barrier might result in proteinuric disease. The glomerular endothelial cells and especially its covering layer, the glycocalyx, play a pivotal role in development of albuminuria. One of the main sulfated glycosaminoglycans in the glomerular endothelial glycocalyx is heparan sulfate. The endoglycosidase heparanase degrades heparan sulfate, thereby affecting glomerular barrier function, immune reactivity and inflammation. Increased expression of glomerular heparanase correlates with loss of glomerular heparan sulfate in many glomerular diseases. Most importantly, heparanase knockout in mice prevented the development of albuminuria after induction of experimental diabetic nephropathy and experimental glomerulonephritis. Therefore, heparanase could serve as a pharmacological target for glomerular diseases. Several factors that regulate heparanase expression and activity have been identified and compounds aiming to inhibit heparanase activity are currently explored.
MeSH term(s)	Albuminuria/enzymology ; Albuminuria/pathology ; Animals ; Diabetic Nephropathies/enzymology ; Diabetic Nephropathies/pathology ; Endothelial Cells/enzymology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Glomerulonephritis/enzymology ; Glomerulonephritis/pathology ; Glucuronidase/metabolism ; Heparitin Sulfate ; Humans ; Kidney Diseases/enzymology ; Kidney Diseases/pathology ; Kidney Glomerulus/enzymology ; Kidney Glomerulus/pathology
Chemical Substances	Heparitin Sulfate (9050-30-0) ; heparanase (EC 3.2.1.-) ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2020-04-07
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-34521-1_26
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Article ; Online: Laminar flow substantially affects the morphology and functional phenotype of glomerular endothelial cells.

't Hart, Daan C / van der Vlag, Johan / Nijenhuis, Tom

PloS one

2021 Volume 16, Issue 5, Page(s) 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. ... ...

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/cm2 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.
MeSH term(s)	Animals ; Antioxidants/metabolism ; Cells, Cultured ; Endothelial Cells/metabolism ; Endothelial Cells/physiology ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/physiology ; Humans ; Inflammation/metabolism ; Inflammation/physiopathology ; Intercellular Adhesion Molecule-1/metabolism ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/physiology ; Mice ; Nitric Oxide/metabolism ; Phenotype ; Stress, Mechanical ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Antioxidants ; Tumor Necrosis Factor-alpha ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2021-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0251129
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Article ; Online: Microparticles in Autoimmunity: Cause or Consequence of Disease?

Rother, Nils / Yanginlar, Cansu / Pieterse, Elmar / Hilbrands, Luuk / van der Vlag, Johan

Frontiers in immunology

2022 Volume 13, Page(s) 822995

Abstract: Microparticles (MPs) are small (100 nm - 1 um) extracellular vesicles derived from the plasma membrane of dying or activated cells. MPs are important mediators of intercellular communication, transporting proteins, nucleic acids and lipids from the ... ...

Abstract	Microparticles (MPs) are small (100 nm - 1 um) extracellular vesicles derived from the plasma membrane of dying or activated cells. MPs are important mediators of intercellular communication, transporting proteins, nucleic acids and lipids from the parent cell to other cells. MPs resemble the state of their parent cells and are easily accessible when released into the blood or urine. MPs also play a role in the pathogenesis of different diseases and are considered as potential biomarkers. MP isolation and characterization is technically challenging and results in different studies are contradictory. Therefore, uniform guidelines to isolate and characterize MPs should be developed. Our understanding of MP biology and how MPs play a role in different pathological mechanisms has greatly advanced in recent years. MPs, especially if derived from apoptotic cells, possess strong immunogenic properties due to the presence of modified proteins and nucleic acids. MPs are often found in patients with autoimmune diseases where MPs for example play a role in the break of immunological tolerance and/or induction of inflammatory conditions. In this review, we describe the main techniques to isolate and characterize MPs, define the characteristics of MPs generated during cell death, illustrate different mechanism of intercellular communication
MeSH term(s)	Autoimmune Diseases/metabolism ; Autoimmunity ; Cell Communication ; Cell-Derived Microparticles/metabolism ; Humans ; Nucleic Acids/metabolism
Chemical Substances	Nucleic Acids
Language	English
Publishing date	2022-04-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.822995
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Article: Heparanase-2 protein and peptides have a protective effect on experimental glomerulonephritis and diabetic nephropathy.

Buijsers, Baranca / Garsen, Marjolein / de Graaf, Mark / Bakker-van Bebber, Marinka / Guo, Chunming / Li, Xue / van der Vlag, Johan

Frontiers in pharmacology

2023 Volume 14, Page(s) 1098184

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1098184
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Article ; Online: Role of dietary interventions on microvascular health in South-Asian Surinamese people with type 2 diabetes in the Netherlands: A randomized controlled trial.

van der Velden, Anouk I M / IJpelaar, Daphne H T / Chandie Shaw, Prataap K / Pijl, Hanno / Vink, Hans / van der Vlag, Johan / Rabelink, Ton J / van den Berg, Bernard M

Nutrition & diabetes

2024 Volume 14, Issue 1, Page(s) 17

Abstract: Background/objectives: We investigated whether dietary interventions, i.e. a fasting mimicking diet (FMD, Prolon®) or glycocalyx mimetic supplementation (Endocalyx: Subjects/methods: A randomized, placebo controlled, 3-arm intervention study was ... ...

Abstract	Background/objectives: We investigated whether dietary interventions, i.e. a fasting mimicking diet (FMD, Prolon®) or glycocalyx mimetic supplementation (Endocalyx Subjects/methods: A randomized, placebo controlled, 3-arm intervention study was conducted in 56 SA-T2DM patients between 18 and 75 years old, for 3 consecutive months, with one additional follow up measurement 3 months after the last intervention. Sublingual microcirculation was assessed with SDF-imaging coupled to the GlycoCheck Results: Despite a temporal improvement in BMI and HbA1c after FMD the major treatment effect on microvascular health was worsening for RBC-velocity independent PBR Conclusions: We showed that despite temporal beneficial changes in BMI and HbA1c after FMD, this intervention is not able to preserve microvascular endothelial health in Dutch South-Asian patients with T2DM. In contrast, glycocalyx mimetics preserves the microvascular endothelial health and reduces the inflammatory cytokine MCP-1. Clinical study registration: NCT03889236.
MeSH term(s)	Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Diabetes Mellitus, Type 2 ; Glycated Hemoglobin ; Netherlands ; Diet ; Caribbean People ; South American People
Chemical Substances	Glycated Hemoglobin
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2609314-5
ISSN	2044-4052 ; 2044-4052
ISSN (online)	2044-4052
ISSN	2044-4052
DOI	10.1038/s41387-024-00275-5
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Article ; Online: Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury.

't Hart, Daan / Li, Jinhua / van der Vlag, Johan / Nijenhuis, Tom

International journal of molecular sciences

2021 Volume 22, Issue 22

Abstract: Increased expression and activity of the ... ...

Abstract	Increased expression and activity of the Ca
MeSH term(s)	Animals ; Calcium Signaling/drug effects ; Cyclic GMP/genetics ; Drug Repositioning ; Endothelial Cells/drug effects ; Guanylate Cyclase/genetics ; Humans ; Kidney Diseases/drug therapy ; Kidney Diseases/genetics ; Kidney Diseases/pathology ; Kidney Glomerulus/drug effects ; Kidney Glomerulus/pathology ; Mice ; Nitric Oxide/genetics ; Paracrine Communication/drug effects ; Podocytes/drug effects ; Podocytes/pathology ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; TRPC6 Cation Channel/genetics
Chemical Substances	Pyrazoles ; Pyrimidines ; TRPC6 Cation Channel ; Nitric Oxide (31C4KY9ESH) ; Guanylate Cyclase (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU) ; riociguat (RU3FE2Y4XI)
Language	English
Publishing date	2021-11-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222212485
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Article ; Online: Novel mouse strains to study circulating permeability factor(s) in primary focal segmental glomerulosclerosis.

den Braanker, Dirk / Maas, Rutger / Parr, Naomi / Deegens, Jeroen / Smeets, Bart / Wetzels, Jack / van der Vlag, Johan / Nijenhuis, Tom

PloS one

2022 Volume 17, Issue 9, Page(s) e0274959

Abstract: Recurrence of proteinuria after kidney transplantation in primary focal segmental glomerulosclerosis (FSGS) is unpredictable. Several putative circulating permeability factors (CPFs) have been suggested, but none have been validated. A clinically ... ...

Abstract	Recurrence of proteinuria after kidney transplantation in primary focal segmental glomerulosclerosis (FSGS) is unpredictable. Several putative circulating permeability factors (CPFs) have been suggested, but none have been validated. A clinically relevant experimental model is required that demonstrates the presence of CPF(s) in patient material, to study CPF(s) and possibly predict recurrence in patients. We aimed to develop a FSGS-prone Thy-1.1 transgenic mouse model with accelerated proteinuria after injection of samples from patients with FSGS. The Thy-1.1 transgene was backcrossed into 5 mouse strains. The age of onset and severity of spontaneous proteinuria varied between the different genetic backgrounds. 129X1/SvThy-1.1 and 129S2/SvPasThy-1.1 mice displayed proteinuria at 4 weeks, whereas Balb/cThy-1.1 and C57BL/6JThy-1.1 mice developed proteinuria from 6 weeks, and were used further. We determined the maximum protein dose that could be injected without causing protein overload in each background. Balb/cThy-1.1 and C57BL/6JThy-1.1 males and females were injected with presumably CPF-containing plasmapheresis effluent from 6 FSGS patients, which induced albuminuria particularly in Balb/cThy-1.1 males. Unfortunately, no response could be detected when using sera instead of plasmapheresis effluent, serum being more clinically relevant in the context of predicting FSGS recurrence. Considering the differences between responses elicited by serum and plasmapheresis effluent, simultaneously collected serum, plasma, and plasmapheresis effluent were tested. Whereas we could detect responses using a validated in vitro model, none of these presumably CPF-containing samples induced proteinuria in Balb/cThy-1.1 males. Thus, we have extensively tested the Thy-1.1 mouse model on different genetic backgrounds with proteinuria after injection of FSGS patient material as clinically relevant readout. The Balb/cThy-1.1 male mouse strain demonstrated the most promising results, but to detect CPF activity in FSGS serum e.g. prior to kidney transplantation, this strain clearly lacks sensitivity and is therefore not yet clinically applicable. It could, however, still be used as research tool to study CPFs in patient samples that did induce proteinuria.
MeSH term(s)	Animals ; Female ; Glomerulosclerosis, Focal Segmental/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Permeability ; Plasmapheresis ; Proteinuria/etiology ; Recurrence
Language	English
Publishing date	2022-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0274959
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Article ; Online: Fasting mimicking diet in diabetic mice partially preserves glomerular endothelial glycocalyx coverage, without changing the diabetic metabolic environment.

van der Velden, Anouk I M / Koudijs, Angela / Kooijman, Sander / Rietjens, Rosalie G J / Sol, Wendy M P J / Avramut, M Cristina / Wang, Gangqi / Rensen, Patrick C N / Rabelink, Ton J / van der Vlag, Johan / van den Berg, Bernard M

American journal of physiology. Renal physiology

2024 Volume 326, Issue 5, Page(s) F681–F693

Abstract: Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced ... ...

Abstract	Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced diabetic apolipoprotein E knockout mouse model whether repeated fasting mimicking diet (FMD) prevents glomerular damage. Diabetic mice received 5 FMD cycles in 10 wk, and during cycles 1 and 5 caloric measurements were performed. After 10 wk, glomerular endothelial morphology was determined together with albuminuria, urinary heparanase-1 activity, and spatial mass spectrometry imaging to identify specific glomerular metabolic dysregulation. During FMD cycles, blood glucose levels dropped while a temporal metabolic switch was observed to increase fatty acid oxidation. Overall body weight at the end of the study was reduced together with albuminuria, although urine production was dramatically increased without affecting urinary heparanase-1 activity. Weight loss was found to be due to lean mass and water, not fat mass. Although capillary loop morphology and endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced together with the presence of UDP-glucuronic acid. Mass spectrometry imaging further revealed reduced protein catabolic breakdown products and increased oxidative stress, not different from diabetic mice. In conclusion, although FMD preserves partially glomerular endothelial glycocalyx, loss of lean mass and increased glomerular oxidative stress argue whether such diet regimes are safe in patients with diabetes.
MeSH term(s)	Animals ; Glycocalyx/metabolism ; Glycocalyx/pathology ; Fasting ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Diabetic Nephropathies/physiopathology ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Oxidative Stress ; Male ; Blood Glucose/metabolism ; Albuminuria/metabolism ; Mice ; Glucuronidase/metabolism ; Mice, Knockout, ApoE ; Mice, Inbred C57BL ; Diet
Chemical Substances	Blood Glucose ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00333.2023
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