Circulating Extracellular Vesicles as Putative Mediators of Cardiovascular Disease in Paediatric Chronic Kidney Disease
Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). However, the pathogenesis of CVD in CKD remains incompletely understood. Endothelial extracellular vesicles (EC-EVs) have previously been associated with CVD. We hypothesized that CKD alters EV release and cargo, subsequently promoting vascular remodelling. We recruited 94 children with CKD, including patients after kidney transplantation and healthy donors, and performed EV phenotyping and functional EV analyses in the absence of age-related comorbidities. Plasma EC-EVs were increased in haemodialysis patients and decreased after kidney transplantation. Thirty microRNAs were less abundant in total CKD plasma EVs with predicted importance in angiogenesis and smooth muscle cell proliferation. In vitro, CKD plasma EVs induced transcriptomic changes in angiogenesis pathways and functionally impaired angiogenic properties, migration and proliferation in ECs. High shear stress, as generated by arterio-venous fistulas, and uremic toxins were considered as potential drivers of EV release, but only the combination increased EV generation from venous ECs. The resulting EVs recapitulated miRNA changes observed in CKD in vivo. In conclusion, CKD results in the release of EVs with altered miRNA profiles and anti-angiogenic properties, which may mediate vascular pathology in children with CKD. EVs and their miRNA cargo may represent future therapeutic targets to attenuate CVD in CKD.
Authors
- Burkhard Kleuser (ORCID: https://orcid.org/0000-0002-1888-9595)
- Nicola Wilck (ORCID: https://orcid.org/0000-0003-3189-5364)
- Katrin Lehmann (ORCID: https://orcid.org/0000-0003-1350-6994)
- Philip Bufler (ORCID: https://orcid.org/0000-0002-5742-8273)
- Dörte Lodka
- Laura Michalick (ORCID: https://orcid.org/0000-0002-3959-5828)
- Harithaa Anandakumar (ORCID: https://orcid.org/0009-0000-3326-5126)
- Christian Hoffmann (ORCID: https://orcid.org/0000-0003-1736-8007)
- Fabian L. Kriegel (ORCID: https://orcid.org/0000-0003-1536-2840)
- Sofia Kirke Forslund (ORCID: https://orcid.org/0000-0003-4285-6993)
- Fabian Schumacher (ORCID: https://orcid.org/0000-0001-8703-3275)
- Pawel Durek (ORCID: https://orcid.org/0000-0002-6179-0670)
- Mir‐Farzin Mashreghi (ORCID: https://orcid.org/0000-0002-8015-6907)
- Wolfgang M. Kuebler (ORCID: https://orcid.org/0000-0003-4100-2961)
- Ulrike Brüning (ORCID: https://orcid.org/0000-0003-0112-4032)
- Benjamin Krause (ORCID: https://orcid.org/0000-0003-4684-2206)
- Frederik Heinrich (ORCID: https://orcid.org/0000-0001-6097-5422)
- István András Szijártó (ORCID: https://orcid.org/0000-0002-0796-9450)
- Hendrik Bartolomaeus (ORCID: https://orcid.org/0000-0003-4288-3828)
- Ulrike Löber (ORCID: https://orcid.org/0000-0001-7468-9531)
- Jennifer Kirwan (ORCID: https://orcid.org/0000-0002-5423-1651)
- Lisa Peters (ORCID: https://orcid.org/0000-0003-3157-6590)
- Andreas Luch (ORCID: https://orcid.org/0000-0002-5866-901X)
- Uwe Querfeld (ORCID: https://orcid.org/0000-0001-6783-3822)
- Toralf Kaiser (ORCID: https://orcid.org/0000-0002-4685-5851)
- Johannes Benjamin Holle (ORCID: https://orcid.org/0000-0001-8032-4096)
- Felix Behrens (ORCID: https://orcid.org/0000-0002-6841-4192)
- Dominik Müller (ORCID: https://orcid.org/0000-0002-3478-1576)
- Laura F. Ginsbach
- Chia‐Yu Chen (ORCID: https://orcid.org/0000-0003-1765-7132)
- Szandor Simmons (ORCID: https://orcid.org/0000-0002-8594-5438)
- André A. Borchardt
- Julia Thumfahrt
Institutions
- St. Michael's Hospital (CA)
- Carl Zeiss (Germany) (DE)
- University of Toronto (CA)
- Max Delbrück Center (DE)
- Federal Institute for Risk Assessment (DE)
- German Rheumatism Research Centre (DE)
- German Centre for Cardiovascular Research (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Journal of Extracellular Vesicles
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1002/jev2.70062
- Citations
- 1
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Bundesministerium für Bildung und Forschung
- Deutsche Stiftung für Herzforschung
- Berlin Institute of Health