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

Area of Science:

• Nephrology
• Cardiology
• Molecular Biology

Background:

• Cardiovascular disease is a leading cause of mortality in chronic kidney disease (CKD) patients.
• Indoxyl sulfate (IS), a protein-bound uremic toxin, accumulates in CKD and promotes cardiovascular disease progression.
• IS-induced endothelial activation leads to the release of endothelial microvesicles (EMVs) that contribute to endothelial dysfunction.

Purpose of the Study:

• To investigate the functional effects of IS-derived EMVs (IsEMVs) on endothelial progenitor cells (EPCs).
• To characterize the miRNA content of IsEMVs and their impact on EPCs' vascular repair capabilities.

Main Methods:

• Developed an in vitro model of IS-mediated endothelial damage.
• Isolated and characterized IsEMVs using ultracentrifugation.
• Assessed the effects of IsEMVs on EPC colony-forming units and in vitro angiogenesis.
• Analyzed miRNA content and key protein expression (NFκB, p53, IκBα) in treated EPCs.

Main Results:

• IS-activated endothelial cells released IsEMVs that modulated EPC functions, including colony formation and angiogenesis.
• IsEMVs contained 23 miRNAs, with four (miR-181a-5p, miR-4454, miR-150-5p, hsa-let-7i-5p) upregulated compared to control EMVs.
• IsEMVs increased NFκB and p53, and decreased IκBα in EPCs, suggesting pro-inflammatory and pro-apoptotic signaling.
• EPCs treated with IsEMVs showed impaired vascular homeostasis.

Conclusions:

• IS induces endothelial vesiculation, generating microvesicles with distinct miRNA profiles and functional consequences.
• IsEMVs impair EPCs' ability to maintain vascular homeostasis and perform repair functions.
• The unique characteristics of IsEMVs suggest their potential as novel biomarkers for diagnosing and predicting vascular disease in CKD patients.