Diabetic nephropathy alters the distribution of circulating angiogenic MicroRNAs among extracellular vesicles, HDL, and Ago-2

Barend W. Florijn, Jacques M.G.J. Duijs, Johannes H. Levels, Geesje M. Dallinga-Thie, Yanan Wang, Anita N. Boing, Yuana Yuana, Wendy Stam, Ronald W.A.L. Limpens, Yu Wah Au, Rienk Nieuwland, Ton J. Rabelink, Marlies E.J. Reinders, Anton Jan Van Zonneveld, Roel Bijkerk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)

Abstract

Previously, we identified plasma microRNA (miR) profiles that associate with markers of microvascular injury in patients with diabetic nephropathy (DN). However, miRs circulate in extracellular vesicles (EVs) or in association with HDL or the RNA-binding protein argonaute-2 (Ago- 2). Given that the EV- and HDL-mediated miR transfer toward endothelial cells (ECs) regulates cellular quiescence and inflammation, we hypothesized that the distribution of miRs among carriers affects microvascular homeostasis in DN. Therefore, we determined the miR expression in EV, HDL, and Ago-2 fractions isolated from EDTA plasma of healthy control subjects, patients with diabetes mellitus (DM) with or without early DN (estimated glomerular filtration rate [eGFR] >30 mL/min/ 1.73 m2), and patients with DN (eGFR <30 mL/min/ 1.73 m2). Consistent with our hypothesis, we observed alterations in miR carrier distribution in plasma of patients with DM and DN compared with healthy control subjects. Both miR-21 and miR-126 increased in EVs of patients with DN, whereas miR-660 increased in the Ago- 2 fraction and miR-132 decreased in the HDL fraction. Moreover, in vitro, differentially expressed miRs improved EC barrier formation (EV-miR-21) and rescued the angiogenic potential (HDL-miR-132) of ECs cultured in serum from patients with DM and DN. In conclusion, miR measurement in EVs, HDL, and Ago-2 may improve the biomarker sensitivity of these miRs for microvascular injury in DN,while carrier-specificmiRs can improve endothelial barrier formation (EV-miR-21/126) or exert a proangiogenic response (HDL-miR-132).

Original languageEnglish
Pages (from-to)2287-2300
Number of pages14
JournalDiabetes
Volume68
Issue number12
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

Bibliographical note

Funding:
This study was supported by an award from the European Foundation
for the Study of Diabetes to A.J.v.Z. and R.B. Additional funding was provided by
the Hartstichting (Netherlands Heart Foundation) in the context of the Queen of
Hearts (2013/T084 to B.W.F. and A.J.v.Z.), CVON RECONNECT (2014/11 to T.J.R.),
and RACE V (2014/09 to A.J.v.Z.) consortia. R.B. is the recipient of a pers

Publisher Copyright:
© 2019 by the American Diabetes Association.

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