MicroRNA-mediated vascular intercellular communication is altered in chronic kidney disease

Area of Science:

• Cardiovascular Biology
• Renal Medicine
• Molecular Biology

Background:

• Chronic kidney disease (CKD) is a significant risk factor for coronary artery disease (CAD).
• Intercellular communication via microRNAs (miRs) within extracellular vesicles (EVs) plays a role in both CKD and CAD.
• The combined impact of CKD and CAD on endothelial function through EV-miRs remains unclear.

Purpose of the Study:

• To investigate the role of EV-incorporated miRs in endothelial dysfunction in patients with combined CAD and CKD.
• To elucidate the molecular mechanisms by which CKD affects EV-miR profiles and endothelial cell function.

Main Methods:

• Comparative analysis of EV-miR levels in patients with CAD, CAD+CKD, and controls.
• Flow cytometry to quantify endothelial cell-derived EVs.
• In vitro studies using human coronary artery endothelial cells (HCAECs) exposed to patient-derived EVs and indoxyl sulfate (IS).
• In vivo mouse model to assess endothelial regeneration after EV treatment.

Main Results:

• CAD+CKD patients exhibited lower levels of vasculo-protective miRs (miR-130a-3p, miR-126-3p) in EVs compared to CAD patients and controls.
• Increased numbers of endothelial cell-derived EVs were observed in CAD and CAD+CKD patients.
• EVs from CAD+CKD patients reduced HCAEC proliferation and re-endothelialization.
• Indoxyl sulfate (IS) exposure decreased miR-130a-3p in EVs, impaired endothelial function, and promoted an anti-angiogenic profile.
• IS induced hnRNPU upregulation, retaining miR-130a-3p intracellularly and reducing its export via EVs.

Conclusions:

• EV-miR mediated vascular intercellular communication is altered in patients with comorbid CAD and CKD.
• CKD-induced changes in EV-miRs contribute to endothelial dysfunction.
• The findings highlight a novel mechanism linking CKD, EV-miRs, and cardiovascular disease progression.