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Diabetic Nephropathy Alters the Distribution of Circulating Angiogenic MicroRNAs Among Extracellular Vesicles, HDL,
Barend W Florijn1,2, Jacques M G J Duijs1,2, Johannes H Levels3
1Department of Internal Medicine (Nephrology), Amsterdam University Medical Center, Amsterdam, the Netherlands.
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-specific miRs can improve endothelial barrier formation (EV-miR-21/126) or exert a proangiogenic response (HDL-miR-132).
Insights
Plasma microRNA (miR) distribution in extracellular vesicles (EVs), HDL, and Ago-2 is altered in diabetic nephropathy (DN). Specific miRs in these carriers impact endothelial cell function, offering potential biomarkers for microvascular injury.
Area of Science:
- Biochemistry
- Molecular Biology
- Nephrology
Background:
- Plasma microRNA (miR) profiles are linked to microvascular injury in diabetic nephropathy (DN).
- MicroRNAs (miRs) are transported via extracellular vesicles (EVs), HDL, and argonaute-2 (Ago-2).
- EV- and HDL-mediated miR transfer influences endothelial cell (EC) quiescence and inflammation.
Purpose of the Study:
- To investigate how miR distribution among carriers (EVs, HDL, Ago-2) affects microvascular homeostasis in diabetic nephropathy (DN).
- To identify specific miRs and their carriers associated with DN and their functional impact on endothelial cells.
Main Methods:
- Isolation of EV, HDL, and Ago-2 fractions from EDTA plasma of healthy controls, diabetes mellitus (DM) patients with/without early DN, and DN patients.
- Quantification of miR expression within these isolated fractions.
- In vitro assessment of differentially expressed miRs on endothelial cell barrier formation and angiogenic potential.
Main Results:
- Significant alterations in miR carrier distribution were observed in patients with DM and DN compared to controls.
- miR-21 and miR-126 increased in EVs of DN patients.
- miR-660 increased in the Ago-2 fraction, and miR-132 decreased in the HDL fraction in DN patients.
- In vitro studies showed EV-miR-21 improved EC barrier function and HDL-miR-132 rescued EC angiogenic potential.
Conclusions:
- Plasma miR measurement in EVs, HDL, and Ago-2 fractions may enhance biomarker sensitivity for microvascular injury in DN.
- Carrier-specific miRs demonstrate functional roles, with EV-miRs (miR-21/126) improving endothelial barrier formation and HDL-miR-132 promoting angiogenesis.
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