Extracellular Vesicles Derived from Endothelial Progenitor Cells Protect Human Glomerular Endothelial Cells and Podocytes from Complement- and Cytokine-Mediated Injury.
Davide MedicaRossana FranzinAlessandra StasiGiuseppe CastellanoMassimiliano MiglioriVincenzo PanichiFederico FiglioliniLoreto GesualdoGiovanni CamussiVincenzo CantaluppiPublished in: Cells (2021)
Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis.
Keyphrases
- high glucose
- endothelial cells
- oxidative stress
- induced apoptosis
- drug resistant
- cell cycle arrest
- vascular endothelial growth factor
- stem cells
- gene expression
- cell migration
- rheumatoid arthritis
- chronic kidney disease
- peripheral blood
- multidrug resistant
- diabetic nephropathy
- dna damage
- signaling pathway
- diabetic rats
- cell death
- endoplasmic reticulum stress
- binding protein
- nitric oxide
- liver failure
- mass spectrometry
- dna methylation
- mesenchymal stem cells
- ischemia reperfusion injury
- cystic fibrosis
- fatty acid
- cell proliferation
- acinetobacter baumannii
- end stage renal disease
- intensive care unit
- staphylococcus aureus
- biofilm formation
- copy number
- quality improvement
- pseudomonas aeruginosa
- protein kinase
- aortic dissection
- candida albicans
- hepatitis b virus
- amino acid