Urinary Exosomal MicroRNAs in Incipient Diabetic Nephropathy

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Abstract

MicroRNAs (miRNAs), a class of small non-protein-encoding RNAs, regulate gene expression via suppression of target mRNAs. MiRNAs are present in body fluids in a remarkable stable form as packaged in microvesicles of endocytic origin, named exosomes. In the present study, we have assessed miRNA expression in urinary exosomes from type 1 diabetic patients with and without incipient diabetic nephropathy. Results showed that miR-130a and miR-145 were enriched, while miR-155 and miR-424 reduced in urinary exosomes from patients with microalbuminuria. Similarly, in an animal model of early experimental diabetic nephropathy, urinary exosomal miR-145 levels were increased and this was paralleled by miR-145 overexpression within the glomeruli. Exposure of cultured mesangial cells to high glucose increased miR-145 content in both mesangial cells and mesangial cells-derived exosomes, providing a potential mechanism for diabetes-induced miR-145 overexpression. In conclusion, urinary exosomal miRNA content is altered in type 1 diabetic patients with incipient diabetic nephropathy and miR-145 may represent a novel candidate biomarker/player in the complication.

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miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

Kimberly Cordes, Neil T. Sheehy, Mark White … (2009)

SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

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MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors.

Mitsuo Kato, Jane Zhang, Mei Wang … (2007)

Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-alpha 1 and -2 (Col1a1 and -2). Transforming growth factor beta1 (TGF-beta), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-beta increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, deltaEF1. TGF-beta treatment or short hairpin RNAs targeting deltaEF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-beta also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to deltaEF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-beta in MMC. TGF-beta treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3' UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with deltaEF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-beta and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-beta-induced Col1a2 expression by down-regulating E-box repressors.

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Exosomes as intercellular signalosomes and pharmacological effectors.

Michel Record, Caroline Subra, Sandrine Silvente-Poirot … (2011)

Cell secretion is a general process involved in various biological responses. Exosomes are part of this process and have gained considerable scientific interest in the past five years. Several steps through investigations across the last 20 years can explain this interest. First characterized during reticulocyte maturation, they were next evidenced as a key player in the immune response and cancer immunotherapy. More recently they were reported as vectors of mRNAs, miRNAs and also lipid mediators able to act on target cells. They are the only type of vesicles released from an intracellular compartment from cells in viable conditions. They appear as a vectorized signaling system operating from inside a donor cell towards either the periphery, the cytosol, or possibly to the nucleus of target cells. Exosomes from normal cells trigger positive effects, whereas those from pathological ones, such as tumor cells or infected ones may trigger non-positive health effects. Therefore regulating the biogenesis and secretion of exosomes appear as a pharmacological challenge to intervene in various pathophysiologies. Exosome biogenesis and molecular content, interaction with target cells, utilisation as biomarkers, and functional effects in various pathophysiologies are considered in this review. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Fabio Martelli: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 4 November 2013

Volume: 8

Issue: 11

Electronic Location Identifier: e73798

Affiliations

[1 ]Diabetic Nephropathy Laboratory, Department of Medical Science, University of Turin, Turin, Italy

[2 ]Renal Research Laboratory, Fondazione IRCCS, Ospedale Maggiore Policlinico and Fondazione D’Amico per la Ricerca sulle Malattie Renali, Milan, Italy

[3 ]MIA Consortium for Image Analysis, Milano Bicocca University, Milan, Italy

[4 ]Department of Biomedical Science and Human Oncology, University of Turin, Turin, Italy

[5 ]Molecular Biotechnology Center (MBC), University of Turin, Turin, Italy

[6 ]Laboratory of Renal and Vascular Pathophysiology, Department of Medical Science, University of Turin, Turin, Italy

IRCCS-Policlinico San Donato, Italy

Author notes

* E-mail: federica.barutta@ 123456unito.it

Competing Interests: The project was founded by the European Federation for the Study of Diabetes, which in turn received funding from a commercial funder Sanofi. Therefore, Sanofi contribution was indirect and we can confirm that this does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: FB GG PCP. Performed the experiments: FB MT AC LA SP SG MCD. Analyzed the data: FB GB. Contributed reagents/materials/analysis tools: DC DT MPR. Wrote the manuscript: FB GG.

Article

Publisher ID: PONE-D-13-07213

DOI: 10.1371/journal.pone.0073798

PMC ID: 3817183

PubMed ID: 24223694

SO-VID: 776b3dc5-899b-4e49-a12d-37af389bf45b

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 19 February 2013

Date accepted : 23 July 2013

Funding

This work was supported by a EFSD & Sanofi European Research Programme in Micro- and Macrovascular Complications of Diabetes Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Urinary Exosomal MicroRNAs in Incipient Diabetic Nephropathy

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Abstract

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PLOS Climate

Most cited references 23

miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors.

Exosomes as intercellular signalosomes and pharmacological effectors.

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