Extracellular vesicles derived from patients with antibody‐mediated rejection induce tubular senescence and endothelial to mesenchymal transition in renal cells. Issue 9 (5th July 2022)

• Record Type: Journal Article
• Authors: Franzin, Rossana; Stasi, Alessandra; Sallustio, Fabio; Bruno, Stefania; Merlotti, Guido; Quaglia, Marco; Grandaliano, Giuseppe; Pontrelli, Paola; Thurman, Joshua M.; Camussi, Giovanni; Stallone, Giovanni; Cantaluppi, Vincenzo; Gesualdo, Loreto; Castellano, Giuseppe
• Is Part Of: American journal of transplantation. Volume 22:Issue 9(2022)
• Page Start: 2139
• Page End: 2157
• Publication Date: 2022-07-05
• Subjects: antibody‐mediated allograft rejection -- aging -- cellular senescence -- complement system -- extracellular vesicles -- miRNA; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.17097
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : Extracellular vesicles (EV) are emerging mediators in several diseases. However, their role in the pathophysiology of antibody‐mediated allograft rejection (AMR) has been poorly investigated. Here, we investigated the role of EV isolated from AMR patients in inducing tubular senescence and endothelial to mesenchymal transition (EndMT) and analyzed their miRNA expression profile. By multiplex bead flow cytometry, we characterized the immunophenotype of plasma AMR‐derived EV and found a prevalent platelet and endothelial cell origin. In vitro, AMR‐derived EV induced tubular senescence by upregulating SA‐β Gal and CDKN1A mRNA. Furthermore, AMR‐derived EV induced EndMT. The occurrence of tubular senescence and EndMT was confirmed by analysis of renal biopsies from the same AMR patients. Moreover, AMR‐derived EV induced C3 gene upregulation and CFH downregulation in tubular epithelial cells, with C4d deposition on endothelial cells. Interestingly, RNase‐mediated digestion of EV cargo completely abrogated tubular senescence and EndMT. By microarray analysis, miR‐604, miR‐515‐3p, miR‐let‐7d‐5p, and miR‐590‐3p were significantly upregulated in EV from AMR group compared with transplant controls, whereas miR‐24‐3p and miR‐29a‐3p were downregulated. Therefore, EV‐associated miRNA could act as active player in AMR pathogenesis, unraveling potential mechanisms of accelerated graft senescence, complement activation and early fibrosis that might lead to new therapeutic intervention. Abstract : Plasma‐derived extracellular vesicles from kidney transplant patients with antibody‐mediated rejection induced endothelial‐to‐mesenchymal transition and senescence in tubular epithelial cells by modulating complement activation. Dieudé and Hébert comment on page 2131