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  1. Article ; Online: Aldosterone: Essential for Life but Damaging to the Vascular Endothelium.

    Crompton, Michael / Skinner, Laura J / Satchell, Simon C / Butler, Matthew J

    Biomolecules

    2023  Volume 13, Issue 6

    Abstract: The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water ...

    Abstract The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium excretion. However, evidence for the pathological impact of excess mineralocorticoid receptor stimulation is increasing. Here, we discussed how in the heart, hyperaldosteronism is associated with fibrosis, cardiac dysfunction, and maladaptive hypertrophy. In the kidney, aldosterone was shown to cause proteinuria and fibrosis and may contribute to the progression of kidney disease. More recently, studies suggested that aldosterone excess damaged endothelial cells. Here, we reviewed how damage to the endothelial glycocalyx may contribute to this process. The endothelial glycocalyx is a heterogenous, negatively charged layer on the luminal surface of cells. Aldosterone exposure alters this layer. The resulting structural changes reduced endothelial reactivity in response to protective shear stress, altered permeability, and increased immune cell trafficking. Finally, we reviewed current therapeutic strategies for limiting endothelial damage and suggested that preventing glycocalyx remodelling in response to aldosterone exposure may provide a novel strategy, free from the serious adverse effect of hyperkalaemia seen in response to mineralocorticoid blockade.
    MeSH term(s) Humans ; Aldosterone/metabolism ; Endothelium, Vascular/metabolism ; Endothelial Cells/metabolism ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Fibrosis
    Chemical Substances Aldosterone (4964P6T9RB) ; Mineralocorticoid Receptor Antagonists
    Language English
    Publishing date 2023-06-17
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom13061004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cerebral microvascular endothelial glycocalyx damage, its implications on the blood-brain barrier and a possible contributor to cognitive impairment.

    Stoddart, Patrice / Satchell, Simon C / Ramnath, Raina

    Brain research

    2022  Volume 1780, Page(s) 147804

    Abstract: The socio-economic impact of diseases associated with cognitive impairment is increasing. According to the Alzheimer's Society there are over 850,000 people with dementia in the UK, costing the UK £26 billion in 2013. Therefore, research into treatment ... ...

    Abstract The socio-economic impact of diseases associated with cognitive impairment is increasing. According to the Alzheimer's Society there are over 850,000 people with dementia in the UK, costing the UK £26 billion in 2013. Therefore, research into treatment of those conditions is vital. Research into the cerebral endothelial glycocalyx (CeGC) could offer effective treatments. The CeGC, consisting of proteoglycans, glycoproteins and glycolipids, is a dynamic structure covering the luminal side oftheendothelial cells of capillaries throughout the body. The CeGC is thicker in cerebral micro vessels, suggesting specialisation for its function as part of the blood-brain barrier (BBB). Recent research evidences that the CeGC is vital in protecting fragile parenchymal tissue and effective functioning of the BBB, as one particularly important CeGC function is to act as a protective barrier and permeability regulator. CeGC degradation is one of the factors which can lead to an increase in BBB permeability. It occurs naturally in aging, nevertheless, premature degradationhas beenevidencedin multipleconditions linked to cognitive impairment, such as inflammation,brain edema, cerebral malaria, Alzheimer's and recently Covid-19. Increasing knowledge of the mechanisms of CeGC damage has led to research into preventative techniques showing that CeGC is a possible diagnostic marker and a therapeutic target. However, the evidence is relatively new, inconsistent and demonstrated mainly in experimental models. This review evaluates the current knowledge of the CeGC, its structure, functions, damage and repair mechanisms and the impact of its degeneration on cognitive impairment in multiple conditions, highlighting the CeGC as a possible diagnostic marker and a potential target for therapeutic treatment.
    MeSH term(s) Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Cognitive Dysfunction/etiology ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/pathology ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Glycocalyx/metabolism ; Glycocalyx/pathology ; Humans ; Microvessels/metabolism ; Microvessels/pathology
    Language English
    Publishing date 2022-01-29
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2022.147804
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The unique structural and functional characteristics of glomerular endothelial cell fenestrations and their potential as a therapeutic target in kidney disease.

    Finch, Natalie C / Neal, Chris R / Welsh, Gavin I / Foster, Rebecca R / Satchell, Simon C

    American journal of physiology. Renal physiology

    2023  Volume 325, Issue 4, Page(s) F465–F478

    Abstract: Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can ... ...

    Abstract Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can contribute to loss of glomerular filtration function. This review provides a comprehensive update of current understanding of the regulation and biogenesis of fenestrae. We consider diseases in which GEnC fenestration loss is recognized or may play a role and discuss methods with potential to facilitate the study of these critical structures. Literature is drawn from GEnCs as well as other fenestrated cell types such as liver sinusoidal endothelial cells that most closely parallel GEnCs.
    MeSH term(s) Humans ; Endothelial Cells/metabolism ; Endothelium ; Kidney Glomerulus/metabolism ; Glomerular Filtration Barrier ; Kidney Diseases/drug therapy ; Kidney Diseases/metabolism
    Language English
    Publishing date 2023-07-20
    Publishing country United States
    Document type Journal Article ; Review ; 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.00036.2023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Glomerular Endothelial Cells: Assessment of Barrier Properties In Vitro.

    Ramnath, Raina D / Satchell, Simon C

    Methods in molecular biology (Clifton, N.J.)

    2019  Volume 2067, Page(s) 145–151

    Abstract: Endothelial cells form the inner lining of all blood vessels and play a vital role in regulating vascular permeability. This applies to the circulation in general and also to specific capillary beds including the renal glomerular capillaries. Endothelial ...

    Abstract Endothelial cells form the inner lining of all blood vessels and play a vital role in regulating vascular permeability. This applies to the circulation in general and also to specific capillary beds including the renal glomerular capillaries. Endothelial dysfunction, including increased permeability, is a key component of diabetes-induced organ damage. Endothelial cells together with their glycocalyx, grown on porous membranes, provide an excellent model to study endothelial permeability properties. Here we describe the measurement of two characteristics of glomerular endothelial cell (GEnC) monolayers: electrical resistance and macromolecular passage. Trans-endothelial electrical resistance provides a measure of small-pore pathways across the endothelium and provides an index of monolayer confluence and cell-cell junction integrity. Measurement of macromolecular passage provides an index of large-pore pathways and use of labeled albumin provides direct relevance to the clinically important parameter of albuminuria. The combination of the two approaches provides a fantastic tool to elucidate endothelial barrier function in vitro including in response to cytokines, pathological stimuli, and potential therapeutic agents.
    MeSH term(s) Albuminuria/pathology ; Biological Assay/instrumentation ; Biological Assay/methods ; Capillaries/cytology ; Capillaries/pathology ; Capillary Permeability/physiology ; Cell Line ; Endothelial Cells/cytology ; Endothelial Cells/pathology ; Endothelium, Vascular/cytology ; Endothelium, Vascular/pathology ; Glomerular Filtration Barrier/cytology ; Glomerular Filtration Barrier/pathology ; Glycocalyx/pathology ; Humans ; Intercellular Junctions/pathology ; Kidney Glomerulus/blood supply ; Kidney Glomerulus/pathology ; Serum Albumin, Human/metabolism
    Chemical Substances Serum Albumin, Human (ZIF514RVZR)
    Language English
    Publishing date 2019-12-02
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-9841-8_11
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Author Correction: The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling.

    Riu, Federica / Slater, Sadie C / Garcia, Eva Jover / Rodriguez-Arabaolaza, Iker / Alvino, Valeria / Avolio, Elisa / Mangialardi, Giuseppe / Cordaro, Andrea / Satchell, Simon / Zebele, Carlo / Caporali, Andrea / Angelini, Gianni / Madeddu, Paolo

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 7132

    Language English
    Publishing date 2024-03-26
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-56932-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Adiponectin reduces glomerular endothelial glycocalyx disruption and restores glomerular barrier function in a mouse model of type 2 diabetes.

    Fawaz, Sarah / Martin Alonso, Aldara / Qiu, Yan / Ramnath, Raina / Stowell-Connolly, Holly / Gamez, Monica / May, Carl / Down, Colin / Coward, Richard J / Butler, Matthew J / Welsh, Gavin I / Satchell, Simon C / Foster, Rebecca R

    Diabetes

    2024  

    Abstract: Adiponectin has vascular anti-inflammatory and protective effects. Whilst adiponectin is known to protect against the development of albuminuria, historically the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The ... ...

    Abstract Adiponectin has vascular anti-inflammatory and protective effects. Whilst adiponectin is known to protect against the development of albuminuria, historically the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnC). In diabetes, eGlx dysfunction occurs before podocyte damage, hence we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signalling in human GEnC through AdipoR1. It significantly reduced eGlx shedding and the TNFα-mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnC in vitro. It protected against increased TNFα mRNA expression in glomeruli isolated from db/db mice, and genes associated with glycocalyx shedding (SDC4, MMP2 and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps'alb) in glomeruli isolated from db/db mice, when administered to mice (i.p) and when applied directly to glomeruli (ex vivo). Ps'alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes.
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db23-0455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The authors reply.

    Ramnath, Raina D / Butler, Matthew J / Foster, Rebecca R / Satchell, Simon C

    Kidney international

    2020  Volume 97, Issue 5, Page(s) 1057–1058

    MeSH term(s) Diabetes Mellitus ; Diabetic Nephropathies ; Glomerular Filtration Barrier ; Glycocalyx ; Humans ; Matrix Metalloproteinases ; Syndecan-4
    Chemical Substances Syndecan-4 ; Matrix Metalloproteinases (EC 3.4.24.-)
    Language English
    Publishing date 2020-04-22
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2020.02.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The glomerular endothelium emerges as a key player in diabetic nephropathy.

    Satchell, Simon C

    Kidney international

    2012  Volume 82, Issue 9, Page(s) 949–951

    Abstract: The effects of diabetes on glomerular structure and particularly that of the glomerular capillary wall have been extensively documented. By correlation with clinical measurements, Weil and colleagues provide important insights into the functional ... ...

    Abstract The effects of diabetes on glomerular structure and particularly that of the glomerular capillary wall have been extensively documented. By correlation with clinical measurements, Weil and colleagues provide important insights into the functional significance of glomerular structural changes in type 2 diabetes. Podocyte detachment correlates with albumin-to-creatinine ratio, but less strongly than does loss of endothelial fenestrations, which also correlates with reduced glomerular filtration rate. The role of the glomerular endothelium in diabetic nephropathy demands further scrutiny.
    MeSH term(s) Diabetes Mellitus, Type 2/pathology ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/pathology ; Female ; Humans ; Kidney Glomerulus/pathology ; Losartan/administration & dosage ; Male ; Podocytes/pathology
    Chemical Substances Losartan (JMS50MPO89)
    Language English
    Publishing date 2012-10-12
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1038/ki.2012.258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: The Pathological Relevance of Increased Endothelial Glycocalyx Permeability.

    Butler, Matthew J / Down, Colin J / Foster, Rebecca R / Satchell, Simon C

    The American journal of pathology

    2020  Volume 190, Issue 4, Page(s) 742–751

    Abstract: The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular ... ...

    Abstract The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular disease has driven research in this area. This review outlines how research to date has attempted to measure the contribution of the endothelial glycocalyx to vessel wall permeability. We discuss the evidence for the role of the endothelial glycocalyx in regulating permeability in discrete areas of the vasculature and highlight the inherent limitations of the data that have been produced to date. In particular, this review emphasizes the difficulties in interpreting urinary albumin levels in early disease models. In addition, the research that supports the view that glycocalyx damage is a key pathologic step in a diverse array of clinical conditions, including diabetic complications, sepsis, preeclampsia, and atherosclerosis, is summarized. Finally, novel methods are discussed, including an ex vivo glomerular permeability assay that enhances the understanding of permeability changes in disease.
    MeSH term(s) Animals ; Capillary Permeability ; Endothelium, Vascular/metabolism ; Glycocalyx/physiology ; Humans ; Vascular Diseases/metabolism ; Vascular Diseases/pathology
    Language English
    Publishing date 2020-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2943-9
    ISSN 1525-2191 ; 0002-9440
    ISSN (online) 1525-2191
    ISSN 0002-9440
    DOI 10.1016/j.ajpath.2019.11.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Visualising the endothelial glycocalyx in dogs.

    Lawrence-Mills, Sara J / Neal, Chris R / Satchell, Simon C / Welsh, Gavin I / Foster, Rebecca R / Finch, Natalie

    Veterinary journal (London, England : 1997)

    2022  Volume 285, Page(s) 105844

    Abstract: The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells. It is critical in maintaining vascular health and when damaged contributes to many diseases. Its fragility makes studying the eGlx technically challenging. The current ... ...

    Abstract The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells. It is critical in maintaining vascular health and when damaged contributes to many diseases. Its fragility makes studying the eGlx technically challenging. The current reference standard for eGlx visualisation, by electron microscopy using glutaraldehyde/Alcian blue perfusion fixation, has not been previously reported in dogs. Established techniques were applied to achieve visualisation of the eGlx in the microvasculature of reproductive tissue in five healthy dogs undergoing elective neutering. Uterine and testicular artery samples underwent perfusion fixation, in the presence of Alcian blue, prior to transmission electron microscopy imaging. Image processing software was used to determine eGlx depth. EGlx was visualised in the arteries of two dogs, one testicular and one uterine, with median (range) eGlx depths of 68.2 nm (32.1-122.9 nm) and 47.6 nm (26.1-129.4 nm) respectively. Study of the eGlx is technically challenging, particularly its direct visualisation in clinical samples. Further research is needed to develop more clinically applicable techniques to measure eGlx health.
    MeSH term(s) Alcian Blue ; Animals ; Dogs ; Endothelial Cells ; Glycocalyx ; Perfusion/veterinary
    Chemical Substances Alcian Blue (P4448TJR7J)
    Language English
    Publishing date 2022-05-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 428614-5
    ISSN 1532-2971 ; 0372-5545 ; 1090-0233
    ISSN (online) 1532-2971
    ISSN 0372-5545 ; 1090-0233
    DOI 10.1016/j.tvjl.2022.105844
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