Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology

Abstract

Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, which can have a major impact in vascular remodeling. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete extracellular vesicles (EVs) that are heterogeneous in terms of their origin and composition. Under physiological conditions, EVs are involved in cell-cell communication and the maintenance of cellular homeostasis. They contain high levels of calcification inhibitors, such as fetuin-A and matrix Gla protein. Under pathological conditions (and particularly in the presence of uremic toxins), the secreted EVs acquire a pro-calcifying profile and thereby act as nucleating foci for the crystallization of hydroxyapatite and the propagation of calcification. Here, we review the most recent findings on the EVs’ pathophysiological role in VC, the impact of uremic toxins on EV biogenesis and functions, the use of EVs as diagnostic biomarkers and the EVs’ therapeutic potential in CKD.

Extracellular Vesicles From LPS-Treated Macrophages Aggravate Smooth Muscle Cell Calcification by Propagating Inflammation and Oxidative Stress

“…Furthermore, an increase in reactive oxygen species (ROS) production is involved in VSMC osteochondrogenic trans-differentiation during the VC process ( Tóth et al, 2020 ; Hu et al, 2021 ). Recent studies have highlighted the role of extracellular vesicles (EVs) in VC ( Hodroge et al, 2017 ; Mansour et al, 2020 ; Yaker et al, 2020 ; Qin et al, 2021 ). These membrane-bound vesicles, secreted by prokaryotic and eukaryotic cells ( Woith et al, 2019 ), can be of various origins, depending on their mode of biogenesis.…”

Pathogenesis of Chronic Kidney Disease Is Closely Bound up with Alzheimer’s Disease, Especially via the Renin-Angiotensin System

“…The irreversible loss of normal renal tissue function and interstitial fibrosis causes pericytes to transdifferentiate into myofibroblasts, followed by massive extracellular matrix deposition and fibrosis and decreased EPO gene transcription [ 28 , 29 , 30 ]. The decline in renal function in CKD blocks the excretion of organic compounds, leading to the accumulation of uremic toxins in the body followed by chronic inflammation, endothelial dysfunction, damage to mitochondria, and oxidative stress [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. The increase in proinflammatory cytokine production, oxidative stress, acidosis, and infections caused by persistent low-grade inflammation results in a dysregulated microvascular response to intrarenal regulators, leading to tubular damage, nephron shedding, and CKD onset [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

“…Glomerulosclerosis decreases downstream peritubular capillary blood flow, causing glomeruli in these areas to secrete excess renin; this further increases circulating angiotensin II (Ang II) levels, which then increases systemic vascular resistance and blood pressure and promotes sodium reabsorption in the proximal tubule and (via aldosterone) the collecting duct [ 53 , 54 , 55 , 56 , 57 , 58 ]. EVs could play an important role in the development of CKD [ 36 , 59 ]; patients with advanced CKD have elevated levels of platelet-, neutrophil-, erythrocyte-, and endothelial cell-derived EVs [ 60 , 61 , 62 ]. Platelet-derived EVs are procoagulant and prothrombotic [ 60 , 62 ], and an increased number of endothelial cell-derived EVs was shown to be correlated with endothelial dysfunction, atherosclerosis, and arterial stiffness [ 63 ].…”

The Contribution of Extracellular Vesicles From Senescent Endothelial and Vascular Smooth Muscle Cells to Vascular Calcification

“…Furthermore, EVs play an essential role in angiogenesis, and together with their role in the development of VSMC senescence and VC generation, they mediate CKD progression and associated cardiovascular complications (96). Moreover, EVs in CKD patients have been proposed as therapeutic targets (97). Thus, the effect on the initiation and progression of VC depends on the number and cargo of EVs generated in patients with chronic inflammatory pathologies.…”