Extracellular vesicles as mediators of vascular inflammation in kidney disease

Abstract

Vascular inflammation is a common cause of renal impairment and a major cause of morbidity and mortality of patients with kidney disease. Current studies consistently show an increase of extracellular vesicles (EVs) in acute vasculitis and in patients with atherosclerosis. Recent research has elucidated mechanisms that mediate vascular wall leukocyte accumulation and differentiation. This review addresses the role of EVs in this process. Part one of this review addresses functional roles of EVs in renal vasculitis. Most published data address anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and indicate that the number of EVs, mostly of platelet origin, is increased in active disease. EVs generated from neutrophils by activation by ANCA can contribute to vessel damage. While EVs are also elevated in other types of autoimmune vasculitis with renal involvement such as systemic lupus erythematodes, functional consequences beyond intravascular thrombosis remain to be established. In typical hemolytic uremic syndrome secondary to infection with shiga toxin producing Escherichia coli , EV numbers are elevated and contribute to toxin distribution into the vascular wall. Part two addresses mechanisms how EVs modulate vascular inflammation in atherosclerosis, a process that is aggravated in uremia. Elevated numbers of circulating endothelial EVs were associated with atherosclerotic complications in a number of studies in patients with and without kidney disease. Uremic endothelial EVs are defective in induction of vascular relaxation. Neutrophil adhesion and transmigration and intravascular thrombus formation are critically modulated by EVs, a process that is amenable to therapeutic interventions. EVs can enhance monocyte adhesion to the endothelium and modulate macrophage differentiation and cytokine production with major influence on the local inflammatory milieu in the plaque. They significantly influence lipid phagocytosis and antigen presentation by mononuclear phagocytes. Finally, platelet, erythrocyte and monocyte EVs cooperate in shaping adaptive T cell immunity. Future research is needed to define changes in uremic EVs and their differential effects on inflammatory leukocytes in the vessel wall.

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…EVs are produced constitutively or upon activation, due to inflammation, hypoxia, oxidative stress, shear stress, senescence, cell death, exposure to bacterial endo/exotoxins, uremia, etc. [10][11][12][13][14][15]. The cargo varies depending on type and differentiation of the parent cell, microenvironmental variables, and agents that triggers EV release.…”

Extracellular Vesicles in Feto–Maternal Crosstalk and Pregnancy Disorders

“…It has been observed that EVs can be released during physiological events in vivo, such as cell growth, proliferation, activation, apoptosis, or senescence. Furthermore, some conditions, such as oxidative or shear stress, inflammation, senescence, and cell death, may also induce EV production [13][14][15][16][17][18]. In any case, EVs are released into the extracellular milieu and finally they could reach the blood circulation.…”

Initiation and Propagation of Vascular Calcification Is Regulated by a Concert of Platelet- and Smooth Muscle Cell-Derived Extracellular Vesicles

“…EVs are highly heterogeneous structures that differ in size, biochemical content and mode of secretion. Current nomenclature distinguishes three populations of EVs: (1) exosomes (30–100 nm), which originate when multivesicular bodies fuse with the plasma membrane, (2) microvesicles/ectosomes (100–1,000 nm), which are generated by budding of the plasma membrane and (3) apoptotic bodies (>1,000 nm), which are formed in the process of programmed cell death ( 2 – 5 ). Each family is composed of small phospholipid membrane-enclosed entities released spontaneously, or, in response to cell activation or apoptosis ( 6 ).…”