Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

Anderson, H. Clarke; Mulhall, Douglas; Garimella, Rama Murthy

doi:10.1038/labinvest.2010.152

Cited by 159 publications

(157 citation statements)

References 103 publications

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“…A wide range of diseases and insults are also associated with the generation of platelet and leukocyte microparticles. 6,20 Injury-associated microparticles provide a surface that may enable initiation of complement activation, and the small size of microparticles may enable them to enter most body fluids. 31,32 Microparticles are present in normal serum and circulate in continuous contact with complement proteins.…”

Section: Discussionmentioning

confidence: 99%

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Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Renner¹,

Klawitter²,

Goldberg³

et al. 2013

Journal of the American Society of Nephrology

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Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

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Section: Discussionmentioning

confidence: 99%

“…6,7 Complement activation on the cell membrane can induce cells to release microparticles. 8,9 Although complement proteins can be detected on the surface of microparticles released from apoptotic and injured cells, 10 less is known regarding whether microparticles from specific cell types themselves can cause complement activation.…”

mentioning

confidence: 99%

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Renner¹,

Klawitter²,

Goldberg³

et al. 2013

Journal of the American Society of Nephrology

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“…(44), and neurons (45). They have recently been studied in different pathological conditions including cancer, atherosclerosis, vascular disease, pulmonary hypertension, and thrombosis as well as bacterial infections (46). Exosomes have been isolated and characterized from many different biological fluids such as blood components, urine, amniotic fluids, malignant effusions, breast milk, and brochoalveolar lavage fluid and contain an array of proteins and lipids as well as genetic material such as mRNA and miRNA (47).…”

Section: Fig 2 Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

Exosomes as Biomarker Enriched Microvesicles: Characterization of Exosomal Proteins Derived from a Panel of Prostate Cell Lines with Distinct AR Phenotypes

Hosseini‐Beheshti

Pham

Adomat

et al. 2012

Molecular & Cellular Proteomics

198

144

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“…Microparticles (also called extracellular vesicles) are submicrometer‐sized membrane vesicles (0.05–1 μm diameter) that are actively shed from cells in response to activation, injury, and apoptosis 15, 16. 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 17, 18, 19, 20, 21, 22.…”

Section: Introductionmentioning

confidence: 99%

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

Jalal

Renner

Laskowski

et al. 2018

JAHA

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BackgroundEndothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD.Methods and ResultsWe analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow–mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post–kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow–mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro.ConclusionThe alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD‐associated vascular disease.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202.

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Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

Cited by 159 publications

References 103 publications

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Exosomes as Biomarker Enriched Microvesicles: Characterization of Exosomal Proteins Derived from a Panel of Prostate Cell Lines with Distinct AR Phenotypes

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

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