Essential role and therapeutic targeting of the glomerular endothelial glycocalyx in lupus nephritis

Kadoya, Hiroyuki; Yu, Ning; Schießl, Ina Maria; Riquier‐Brison, Anne; Gyarmati, Georgina; Desposito, Dorinne; Kidokoro, Kengo; Butler, Matthew; Jacob, Chaim O.; Peti‐Peterdi, Janos

doi:10.1172/jci.insight.131252

Cited by 18 publications

(47 citation statements)

References 65 publications

(82 reference statements)

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“…This glycocalyx accumulation involved its hyaluronic acid component and appeared to be specific to LN, since other inflammatory conditions such as diabetes were associated with diminished glycocalyx as described before (16,21). Glomerular immune cell homing, local inflammation, glomerular albumin leakage, and albuminuria observed in these LN mouse models were mediated via the binding of CD44 (expressed on the surface of activated memory T cells) to its ligand hyaluronic acid present in excess in the GEnC glycocalyx (21). Importantly, treatment with different glycocalyx degrading enzymes reduced glycocalyx thickness back to normal levels (rather than completely eliminating it), disrupted immune cell homing, improved clinical LN including albuminuria and animal survival (21).…”

Section: Endothelial Surface Layer (Glycocalyx) Controls Glomerular Homing Of Immune Cells and Proteinuriamentioning

confidence: 61%

“…Rich in proteoglycans and secreted glycosaminoglycans (e.g., heparan sulfate and hyaluronic acid), the GEnC glycocalyx has important roles in several processes including restricting albumin passage through the GFB, binding chemokines and growth factors, and immune cell adhesion (2,24,25). Intravital MPM imaging approaches have successfully visualized these GEnC structures and functions in the intact living kidney including the bulk fluid flow in fenestrated capillaries (11,26) and the presence and alterations in GEnC glycocalyx in various disease models (15,(19)(20)(21).…”

Section: Endothelial Injury Microthrombi Hemodynamic and Mechanical Factors In Albumin Leakagementioning

confidence: 99%

“…However, recent major improvements in laser and microscopy technologies have made it possible to routinely image deep cortical glomeruli in the intact mouse kidney (17). Most of the new knowledge and topics reviewed here were derived from using these recent state-of-the-art MPM imaging approaches in intact adult mouse kidneys up to 8months of age (Figures 1, 2) (18)(19)(20)(21)(22). Importantly, MPM has been able to directly visualize (patho)physiological processes of the entire glomerulus, the many elements of the GFB simultaneously as parts of the whole functional unit rather than just focusing on a single cell type (12,14).…”

Section: Introductionmentioning

confidence: 99%

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New Endothelial Mechanisms in Glomerular (Patho)biology and Proteinuria Development Captured by Intravital Multiphoton Imaging

2021

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In the past two decades, intravital imaging using multiphoton microscopy has provided numerous new visual and mechanistic insights into glomerular biology and disease processes including the function of glomerular endothelial cells (GEnC), podocytes, and the development of proteinuria. Although glomerular endothelial injury is known to precede podocyte damage in several renal diseases, the primary role of GEnCs in proteinuria development received much less attention compared to the vast field of podocyte pathobiology. Consequently, our knowledge of GEnC mechanisms in glomerular diseases is still emerging. This review highlights new visual clues on molecular and cellular mechanisms of GEnCs and their crosstalk with podocytes and immune cells that were acquired recently by the application of multiphoton imaging of the intact glomerular microenvironment in various proteinuric disease models. New mechanisms of glomerular tissue remodeling and regeneration are discussed based on results of tracking the fate and function of individual GEnCs using serial intravital multiphoton imaging over several days and weeks. The three main topics of this review include (i) the role of endothelial injury and microthrombi in podocyte detachment and albumin leakage via hemodynamic and mechanical forces, (ii) the alterations of the endothelial surface layer (glycocalyx) and its interactions with circulating immune cells in lupus nephritis, and (iii) the structural and functional remodeling and regeneration of GEnCs in hypertension, diabetes, and other experimental injury conditions. By the comprehensive visual portrayal of GEnCs and the many other contributing glomerular cell types, this review emphasizes the complexity of pathogenic mechanisms that result in proteinuria development.

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Section: Endothelial Surface Layer (Glycocalyx) Controls Glomerular Homing Of Immune Cells and Proteinuriamentioning

confidence: 61%

Section: Endothelial Injury Microthrombi Hemodynamic and Mechanical Factors In Albumin Leakagementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New Endothelial Mechanisms in Glomerular (Patho)biology and Proteinuria Development Captured by Intravital Multiphoton Imaging

2021

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“…by retro-orbital injections to label the circulating plasma. To visualize the endothelial surface layer, 2µg/g BW of Alexa Fluor 488-conjugated wheat germ agglutinin (Thermo Fischer Scientific) was injected iv as described before (52). The animals were placed on the microscope stage and body temperature was maintained with a homeothermic blanket system (Harvard Apparatus) as described previously (29,30,53).…”

Section: Serial Intravital Mpm Imagingmentioning

confidence: 99%

Serial intravital imaging captures dynamic and functional endothelial remodeling with single-cell resolution

Desposito¹,

Schießl²,

Gyarmati³

et al. 2021

JCI Insight

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Endothelial cells are important in the maintenance of healthy blood vessels and in the development of vascular diseases. However, the origin and dynamics of endothelial precursors and remodeling at the single-cell level have been difficult to study in vivo due to technical limitations. We aimed to develop a direct visual approach to track the fate and function of single endothelial cells over several days-weeks in the same vascular bed in vivo using multiphoton microscopy (MPM) of transgenic Cdh5-Confetti mice and the kidney glomerulus as a model. Individual cells of the vascular endothelial lineage were identified and tracked due to their unique color combination, based on the random expression of cyan/green/yellow/red fluorescent proteins. Experimental hypertension, hyperglycemia, and laser-induced endothelial cell ablation rapidly increased the number of new glomerular endothelial cells that appeared in clusters of the same color, suggesting clonal cell remodeling by local precursors at the vascular pole. Furthermore, intravital MPM allowed the detection of distinct structural and functional alterations of proliferating endothelial cells. No circulating Cdh5-Confetti + cells were found in the renal cortex. The heart, lung, and kidneys showed more significant clonal endothelial cell expansion compared to the brain, pancreas, liver and spleen. Serial MPM of Cdh5-Confetti mice in vivo is a powerful new technical advance to study endothelial remodeling and repair in the kidney and other organs under physiological and disease conditions.

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“…The GEC and the GEC surface layer (also known as the glycocalyx) are the first points of contact with the components of the circulating immune system. T cells are recruited to the glomerulus via the direct binding of their CD44 to the hyaluronic acid (HA) component of GEC glycocalyx (39). ICs alter cell morphology, up-regulate active caspase-3' expression, inhibit angiogenesis, and increase NO production in GECs (40).…”

Section: Glomerulus Lossmentioning

confidence: 99%

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

Ding

Ren

2021

Front. Immunol.

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Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

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Essential role and therapeutic targeting of the glomerular endothelial glycocalyx in lupus nephritis

Cited by 18 publications

References 65 publications

New Endothelial Mechanisms in Glomerular (Patho)biology and Proteinuria Development Captured by Intravital Multiphoton Imaging

New Endothelial Mechanisms in Glomerular (Patho)biology and Proteinuria Development Captured by Intravital Multiphoton Imaging

Serial intravital imaging captures dynamic and functional endothelial remodeling with single-cell resolution

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

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