Insights into the Diagnostic Potential of Extracellular Vesicles and their miRNA Signature from Liquid Biopsy as Early Biomarkers of Diabetic Micro/Macrovascular Complications

Marca, Valeria La; Fierabracci, Alessandra

doi:10.20944/preprints201709.0027.v1

Cited by 27 publications

(35 citation statements)

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“…Recent studies have indicated that HSA could promote renal tubular epithelial cell EMT and ER stress (LaMarca & Fierabracci, 2017). To determine whether miR-4756 can modulate the EMT and ER stress processes in HSA-induced HK-2 cells, we transfected HK-2 cells with an miR-4756 mimic(Figure 2a).…”

mentioning

confidence: 99%

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

Jia

Zheng

Yang

et al. 2018

Journal Cellular Physiology

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Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR-4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We then found that miR-4756 targeted the 3'-untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased 5' monophosphate-activated protein kinase activation. Thus, our study provides evidence that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR-4756 may be a novel strategy for DKD treatment.

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mentioning

confidence: 99%

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

Jia

Zheng

Yang

et al. 2018

Journal Cellular Physiology

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“…Interaction between MVs and recipient cells operates through two main mechanisms: (a) receptor‐ligand interaction— interaction between specific ligands on MVs surface and receptors on target cells leads to subsequent cascade responses; and (b) direct transferring part of their content or component to target cells . When MVs interact with target cells, perhaps the two mechanisms can influence each other.…”

Section: Mirnas Are Found In Mvs and Transferred Between Cellsmentioning

confidence: 99%

“…On the one hand, extracellular miRNAs hold great potential to act as disease biomarkers due to their non-invasive accessibility and remarkable stability. 60,77,129 A great number of studies have shown that miRNAs are differently enriched in MVs, and their expression patterns also change with respect to different diseases. 130 Therefore, MVs and associated miRNAs are considered to be potential diagnostic biomarkers of diseases.…”

Section: The Clinical Prospect Of Mvsmentioning

confidence: 99%

The role of microvesicles containing microRNAs in vascular endothelial dysfunction

Shu

Tan

Miao

et al. 2019

J Cellular Molecular Medi

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Many studies have shown that endothelial dysfunction is associated with a variety of cardiovascular diseases. The endothelium is one of the primary targets of circulating microvesicles. Besides, microRNAs emerge as important regulators of endothelial cell function. As a delivery system of microRNAs, microvesicles play an active and important role in regulating vascular endothelial function. In recent years, some studies have shown that microvesicles containing microRNAs regulate the pathophysiological changes in vascular endothelium, such as cell apoptosis, proliferation, migration and inflammation. These studies have provided some clues for the possible roles of microvesicles and microRNAs in vascular endothelial dysfunction‐associated diseases, and opened the door towards discovering potential novel therapeutic targets. In this review, we provide an overview of the main characteristics of microvesicles and microRNAs, summarizing their potential role and mechanism in endothelial dysfunction, and discussing the clinical application and existing problems of microvesicles for better translational applications.

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“…While increasing numbers of studies have focused on the potential roles of circulating MPs as diagnostic tools (Berezin et al . ; La Marca & Fierabracci, ; Michalska‐Jakubus et al . ; Pasquier et al .…”

Section: Introductionmentioning

confidence: 99%

“…MPs, the small plasma membrane-derived vesicles released during cell activation and apoptosis, often retain membrane surface molecules, cytoplasmic proteins, lipids and nucleic acids from their parent cells, and have been recognized as important biomarkers of disease status. While increasing numbers of studies have focused on the potential roles of circulating MPs as diagnostic tools La Marca & Fierabracci, 2017;Michalska-Jakubus et al 2017;Pasquier et al 2017;Ridger et al 2017;Hosseinzadeh et al 2018), their precise impact on the pathogenesis and progression of diseases remains obscure (Nomura et al 2008). Currently, functional MP studies have been conducted mainly on specific cell type-derived MPs using in vitro approaches (Leroyer et al 2008;Badimon et al 2017;Burger et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

Feng

Stork

et al. 2019

The Journal of Physiology

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Key points Circulating microparticles (MPs) are elevated in many cardiovascular diseases and have been considered as biomarkers of disease prognosis; however, current knowledge of MP functions has been mainly derived from in vitro studies and their precise impact on vascular inflammation and disease progression remains obscure. Using a diabetic rat model, we identified a >130‐fold increase in MPs in plasma of diabetic rats compared to normal rats, the majority of which circulated as aggregates, expressing multiple cell markers and largely externalized phosphatidylserine; vascular images illustrate MP biogenesis and their manifestations in microvessels of diabetic rats. Using combined single microvessel perfusion and systemic cross‐transfusion approaches, we delineated how diabetic MPs propagate inflammation in the vasculature and transform normal microvessels into an inflammatory phenotype observed in the microvessels of diabetic rats. Our observations derived from animal studies resembling conditions in diabetic patients, providing a mechanistic insight into MP‐mediated pathogenesis of diabetes‐associated multi‐organ microvascular dysfunction. Abstract In various cardiovascular diseases, microparticles (MPs), the membrane‐derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely derived from in vitro studies. The precise impact of disease‐induced MPs on vascular inflammation and disease progression remains obscure. In this study we investigated the biogenesis, profile and functional roles of circulating MPs using a streptozotocin‐induced diabetic rat model with well‐characterized microvascular functions. Our study revealed a >130‐fold increase in MPs in the plasma of diabetic rats compared to normal rats. The majority of these MPs originate from platelets, leukocytes and endothelial cells (ECs), and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre‐coated with a lipid‐binding protein, annexin V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi‐organ vascular dysfunction that commonly occurs in diabetic patients.

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Insights into the Diagnostic Potential of Extracellular Vesicles and their miRNA Signature from Liquid Biopsy as Early Biomarkers of Diabetic Micro/Macrovascular Complications

Cited by 27 publications

References 1 publication

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

The role of microvesicles containing microRNAs in vascular endothelial dysfunction

Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

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