Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

Jalal, Diana; Renner, Brandon; Laskowski, Jennifer; Stites, Erik; Cooper, James E.; Valente, Karissa; You, Zhiying; Perrenoud, Loni; Quintrec, Moglie Le; Muhamed, Ismaeel; Christians, Uwe; Klawitter, Jelena; Lindorfer, Margaret A.; Taylor, Ronald P.; Holers, V. Michael; Thurman, Joshua M.

doi:10.1161/jaha.117.007818

Cited by 46 publications

(40 citation statements)

References 54 publications

(53 reference statements)

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“…MVs released by cells exposed to uremic substances promote functional loss in endothelial progenitor cells (marked by overexpression of NF-κB and p53 proteins) (Carmona et al, 2017b) and TGFβ-mediated proliferation of vascular smooth muscle cells (Ryu et al, 2017), while isolated ESRD MVs can impair NO release and endothelium relaxation (Amabile et al, 2005). Endothelial dysfunction may be further related to activation of the alternative complement pathway and of note, endothelium-derived MVs in CKD do contain factor D and can activate the alternative pathway in vitro (Jalal et al, 2018).…”

Section: What Is the Message Of Circulating Evs In Ckd?mentioning

confidence: 99%

The Multi-Faced Extracellular Vesicles in the Plasma of Chronic Kidney Disease Patients

Georgatzakou

Pavlou

Papageorgiou

et al. 2020

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cells in body fluids and extracellular matrix. They function as signal transducers in intercellular communication, contributing to the maintenance of cell and tissue integrity. EVs biogenesis is deregulated in various pathologies, in structural and functional connection to the pathophysiology of donor cells. Consequently, EVs are considered diagnostic and monitoring factors in many diseases. Despite consensus as to their activity in promoting coagulation and inflammation, there is evidence suggesting protective roles for EVs in stress states. Chronic kidney disease (CKD) patients are at high risk of developing cardiovascular defects. The pathophysiology, comorbidities, and treatment of CKD may individually and in synergy affect extracellular vesiculation in the kidney, endothelium, and blood cells. Oxidative and mechanical stresses, chronic inflammation, and deregulation of calcium and phosphate homeostasis are established stressors of EV release. EVs may affect the clinical severity of CKD by transferring biological response modifiers between renal, vascular, blood, and inflammatory cells. In this Review, we focus on EVs circulating in the plasma of CKD patients. We highlight some recent advances in the understanding of their biogenesis, the effects of dialysis, and pharmacological treatments on them and their potential impact on thrombosis and vascular defects. The strong interest of the scientific community to this exciting field of research may reveal hidden pieces in the pathophysiology of CKD and thus, innovative ways to treat it. Overcoming gaps in EV biology and technical difficulties related to their size and heterogeneity will define the success of the project.

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Section: What Is the Message Of Circulating Evs In Ckd?mentioning

confidence: 99%

The Multi-Faced Extracellular Vesicles in the Plasma of Chronic Kidney Disease Patients

Georgatzakou

Pavlou

Papageorgiou

et al. 2020

Front. Cell Dev. Biol.

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“…Several studies highlighted the interactions between complement and the endothelium in pathogenesis of different renal diseases, including IRI, hemolytic uremic syndrome, and renal allograft injury (224). During inflammation, endothelium is continuously exposed to autologous complement (225) generated by the local or systemic activation of all complement pathways.…”

Section: Endothelial Cells and Complement Systemmentioning

confidence: 99%

“…A number of recent studies have shown that diseases of the vasculature and kidneys, including CKD, are associated with increased numbers of circulating endothelial microparticles and complement activation (224). EVs are actively shed from cells in response to injury.…”

Section: Endothelial Cells and Complement Systemmentioning

confidence: 99%

“…In particular, the microparticles found in the plasma of CKD patients presented increased levels of factor D that contributes to alternative pathway activation and systemic inflammation. Interfering with complement activation and microparticle release may be a potential therapeutic strategy to ameliorate kidney dysfunction in these patients (224).…”

Section: Endothelial Cells and Complement Systemmentioning

confidence: 99%

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Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

et al. 2020

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The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

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“…In uremic conditions, it was demonstrated that PCS, IS, and inorganic phosphate induced the formation of EMPs from endothelial cells [ 113 , 163 , 167 , 168 , 169 ]. Studies have also shown that EMPs are related to endothelial dysfunction in CKD patients [ 17 , 167 , 170 , 171 ]. In vitro, Carmona et al [ 163 ] showed that EMPs from endothelial cells exposed to IS had increased levels of ICAM-1 and PECAM-1, and miRNAs (e.g., miR-181a-5p, miR-4454, and miR-150-5p).…”

Section: Uremic Toxins Induce the Formation Of Endothelial Micropamentioning

confidence: 99%

How do Uremic Toxins Affect the Endothelium?

Cunha

Santos

Barreto

et al. 2020

Toxins

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Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell–cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.

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Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

Cited by 46 publications

References 54 publications

The Multi-Faced Extracellular Vesicles in the Plasma of Chronic Kidney Disease Patients

The Multi-Faced Extracellular Vesicles in the Plasma of Chronic Kidney Disease Patients

Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

How do Uremic Toxins Affect the Endothelium?

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