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Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction.

ABSTRACT: Cardiovascular disease is a major cause of mortality in chronic kidney disease patients. Indoxyl sulfate (IS) is a typical protein-bound uremic toxin that cannot be effectively cleared by conventional dialysis. Increased IS is associated with the progression of chronic kidney disease and development of cardiovascular disease. After endothelial activation by IS, cells release endothelial microvesicles (EMV) that can induce endothelial dysfunction. We developed an in vitro model of endothelial damage mediated by IS to evaluate the functional effect of EMV on the endothelial repair process developed by endothelial progenitor cells (EPCs). EMV derived from IS-treated endothelial cells were isolated by ultracentrifugation and characterized for miRNAs content. The effects of EMV on healthy EPCs in culture were studied. We observed that IS activates endothelial cells and the generated microvesicles (IsEMV) can modulate the classic endothelial roles of progenitor cells as colony forming units and form new vessels in vitro. Moreover, 23 miRNAs were contained in IsEMV including four (miR-181a-5p, miR-4454, miR-150-5p, and hsa-let-7i-5p) that were upregulated in IsEMV compared with control endothelial microvesicles. Other authors have found that miR-181a-5p, miR-4454, and miR-150-5p are involved in promoting inflammation, apoptosis, and cellular senescence. Interestingly, we observed an increase in NF?B and p53, and a decrease in I?B? in EPCs treated with IsEMV. Our data suggest that IS is capable of inducing endothelial vesiculation with different membrane characteristics, miRNAs and other molecules, which makes maintaining of vascular homeostasis of EPCs not fully functional. These specific characteristics of EMV could be used as novel biomarkers for diagnosis and prognosis of vascular disease.

SUBMITTER: Carmona A

PROVIDER: S-EPMC5599774 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction.

Carmona Andres A Guerrero Fatima F Buendia Paula P Obrero Teresa T Aljama Pedro P Carracedo Julia J

Frontiers in physiology 20170908

Cardiovascular disease is a major cause of mortality in chronic kidney disease patients. Indoxyl sulfate (IS) is a typical protein-bound uremic toxin that cannot be effectively cleared by conventional dialysis. Increased IS is associated with the progression of chronic kidney disease and development of cardiovascular disease. After endothelial activation by IS, cells release endothelial microvesicles (EMV) that can induce endothelial dysfunction. We developed an <i>in vitro</i> model of endothel ...[more]

PMID: 28951723

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Project description:Introduction: Cardiovascular pathology is the main cause of death in patients with chronic kidney disease (CKD). CKD is associated with the accumulation of uremic toxins in the bloodstream due to their difficult elimination by renal substitution therapy. Indoxyl sulfate (IS) is one of the most abundant uremic toxins found in the blood of patients with CKD. We conducted an in vitro study to assess the mechanisms underlying IS-induced endothelial dysfunction that could lead to cardiovascular diseases. We studied not only endothelial cells but also their extracellular vesicles (EVs) owing to their capacity to act as messengers that transmit signals through their cargo. Methods: EVs were characterized using nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry, and their tetraspanin expression was evaluated to confirm their identity as EVs. Subsequently, mass spectrophotometry of the protein lysates of cells and EVs was performed, followed by Gene Set Enrichment Analysis to identify the principal altered pathways. Additionally, qPCR and proliferation analyses were performed to confirm proteomic results. Results: Proteomic analysis of endothelial cells revealed that IS causes an increase in proteins related to adipogenesis, inflammation, and xenobiotic metabolism and a decrease in proliferation via mTOR. Inflammation due to TNF signaling via NFкB was confirmed by an increase in the expression of the target genes IL-6, MCP-1, and ICAM-1. Concerning EVs, extracellular matrix elements were reduced, and myogenesis genes were downregulated in response to UV irradiation and inflammation. Fatty acid metabolism also seemingly increases, which, along with adipogenesis and inflammation observed in cells, could be related to atherosclerosis. Conclusions: Endothelial cells treated with IS had more proteins related to adipogenesis, inflammation, and xenobiotic metabolism and fewer associated with proliferation. Furthermore, EVs from cells treated with IS may mediate endothelial dysfunction, since they present fewer extracellular matrix elements, myogenesis and inflammatory factors, and proteins downregulated in response to UV radiation.

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Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction.

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Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction.

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