The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?

Duni, Anila; Liakopoulos, Vassilios; Koutlas, Vasileios; Pappas, Charalampos; Mitsis, Michalis; Dounousi, Evangelia

doi:10.3390/ijms22042157

Cited by 21 publications

(14 citation statements)

References 151 publications

(89 reference statements)

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“…In order to exert flow conditions, we established a BioStat mock circulation, which was designed to simulate BHL relevant, clinical settings [28], imitating various pO 2 and pCO 2 blood levels as seen in patients suffering from different lung diseases, or rather different flow dynamics during disease dependent BHL application, e.g., veno-venous or rather veno-arterial [41] cannulation, providing the important pre-translational test platform for BHL assessment under these disease-like conditions. However, the set-up used in this study ensured constant arterial blood parameters under the applied flow conditions, to exclude any detrimental effects on the EC monolayer behavior, e.g., glycocalyx degradation, as seen for example in ischemia and reperfusion injury [42] or rather ROS (reactive oxygen species) production, which occurs during hyperoxemia and adversely triggers pro-inflammatory cell responses or even induces apoptosis [43].…”

Section: Discussionmentioning

confidence: 99%

Towards Biohybrid Lung Development—Fibronectin-Coating Bestows Hemocompatibility of Gas Exchange Hollow Fiber Membranes by Improving Flow-Resistant Endothelialization

et al. 2021

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To provide an alternative treatment option for patients with end-stage lung disease, we aim for biohybrid lung development (BHL) based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. For long-term BHL application, complete hemocompatibility of all blood-contacting surfaces is indispensable and can be achieved by their endothelialization. Indeed, albumin/heparin (AH) coated HFM enables initial endothelialization, but as inexplicable cell loss under flow conditions was seen, we assessed an alternative HFM coating using fibronectin (FN). Therefore, endothelial cell (EC) adherence and viability on both coated HFM were analyzed by fluorescence-based staining. Functional leukocyte and thrombocyte adhesion assays were performed to evaluate hemocompatibility, also in comparison to blood plasma coated HFM as a clinically relevant control. To assess monolayer resistance and EC behavior under clinically relevant flow conditions, a mock circulation setup was established, which also facilitates imitation of lung-disease specific blood gas settings. Besides quantification of flow-associated cell loss, endothelial responses towards external stimuli, like flow exposure or TNFα stimulation, were analyzed by qRT-PCR, focusing on inflammation, thrombus formation and extracellular matrix production. Under static conditions, both coated HFM enabled the generation of a viable, confluent, non-inflammatory and anti-thrombogenic monolayer. However, by means of homogenous FN coating, cell retention and physiologic gene regulation towards an improved hemocompatible-and extracellular matrix producing phenotype, was significantly superior compared to the inhomogeneous AH coating. In summary, our adaptable in-house FN coating secures the endothelial requirements for long-term BHL application and may promote monolayer establishment on all other blood contacting surfaces of the BHL (e.g., cannulae).

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Section: Discussionmentioning

confidence: 99%

Towards Biohybrid Lung Development—Fibronectin-Coating Bestows Hemocompatibility of Gas Exchange Hollow Fiber Membranes by Improving Flow-Resistant Endothelialization

et al. 2021

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“…The increased mRNA expression levels may be compensatory of the increased shedding of proteins ( 168 ). Syndecan shedding is observed in response to thrombin activation ( 166 , 169 ), hypoxia, ischemia-reperfusion injury ( 170 ) and in preeclampsia ( 171 ). In glomerular EC, syndecan-4 shedding in response to IL-1β activation and was mediated by matrix metalloproteinase-9 ( 127 ).…”

Section: Molecular Components Of the Ec Glycocalyxmentioning

confidence: 99%

The Glomerular Endothelium Restricts Albumin Filtration

2021

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Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.

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“…Most glycocalyx-related proteins penetrate cell membranes and attach to the cytoskeleton. This linkage is structured not only to limit the position and form the basis of the glycocalyx structure but also to facilitate signal transduction across the cell membrane [ 7 , 8 ]. Syndecan (SDC) is a glycoprotein of the glycocalyx that is tightly bound through the membrane-spanning domain [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Ulinastatin on Syndecan-2-Mediated Vascular Damage in IDH2-Deficient Endothelial Cells

et al. 2022

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Syndecan-2 (SDC2), a cell-surface heparin sulfate proteoglycan of the glycocalyx, is mainly expressed in endothelial cells. Although oxidative stress and inflammatory mediators have been shown to mediate dysfunction of the glycocalyx, little is known about their role in vascular endothelial cells. In this study, we aimed to identify the mechanism that regulates SDC2 expression in isocitrate dehydrogenase 2 (IDH2)-deficient endothelial cells, and to investigate the effect of ulinastatin (UTI) on this mechanism. We showed that knockdown of IDH2 induced SDC2 expression in human umbilical vein endothelial cells (HUVECs). Matrix metalloproteinase 7 (MMP7) influences SDC2 expression. When IDH2 was downregulated, MMP7 expression was increased, as was TGF-β signaling, which regulates MMP7. Inhibition of MMP7 activity using MMP inhibitor II significantly reduced SDC2, suggesting that IDH2 mediated SDC2 expression via MMP7. Moreover, expression of SDC2 and MMP7, as well as TGF-β signaling, increased in response to IDH2 deficiency, and treatment with UTI reversed this increase. Similarly, the increase in SDC2, MMP7, and TGF-β signaling in the aorta of IDH2 knockout mice was reversed by UTI treatment. These findings suggest that IDH2 deficiency induces SDC2 expression via TGF-β and MMP7 signaling in endothelial cells.

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The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?

Cited by 21 publications

References 151 publications

Towards Biohybrid Lung Development—Fibronectin-Coating Bestows Hemocompatibility of Gas Exchange Hollow Fiber Membranes by Improving Flow-Resistant Endothelialization

Towards Biohybrid Lung Development—Fibronectin-Coating Bestows Hemocompatibility of Gas Exchange Hollow Fiber Membranes by Improving Flow-Resistant Endothelialization

The Glomerular Endothelium Restricts Albumin Filtration

Effect of Ulinastatin on Syndecan-2-Mediated Vascular Damage in IDH2-Deficient Endothelial Cells

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