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Urinary exosomal microRNAs in incipient diabetic nephropathy.

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.

SUBMITTER: Barutta F

PROVIDER: S-EPMC3817183 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Urinary exosomal microRNAs in incipient diabetic nephropathy.

Barutta Federica F Tricarico Marinella M Corbelli Alessandro A Annaratone Laura L Pinach Silvia S Grimaldi Serena S Bruno Graziella G Cimino Daniela D Taverna Daniela D Deregibus Maria Chiara MC Rastaldi Maria Pia MP Perin Paolo Cavallo PC Gruden Gabriella G

PloS one 20131104 11

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 ur ...[more]

PMID: 24223694

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Project description:BackgroundDespite major advances in the treatment of diabetic nephropathy (DN) in recent years, it remains the most common cause of end-stage renal disease. An early diagnosis and therapy may slow down the DN progression. Numerous potential biomarkers are currently being researched. Circulating levels of the kidney-released exosomes and biological molecules, which reflect the DN pathology including glomerular and tubular dysfunction as well as mesangial expansion and fibrosis, have shown the potential for predicting the occurrence and progression of DN. Moreover, many experimental therapies are currently being investigated, including stem cell therapy and medications targeting inflammatory, oxidant, or pro-fibrotic pathways activated during the DN progression. The therapeutic potential of stem cells is partly depending on their secretory capacity, particularly exosomal microRNAs (Exo-miRs). In recent years, a growing line of research has shown the participation of Exo-miRs in the pathophysiological processes of DN, which may provide effective therapeutic and biomarker tools for DN treatment.MethodsA systematic literature search was performed in MEDLINE, Scopus, and Google Scholar to collect published findings regarding therapeutic stem cell-derived Exo-miRs for DN treatment as well as circulating Exo-miRs as potential DN-associated biomarkers.FindingsGlomerular mesangial cells and podocytes are the most important culprits in the pathogenesis of DN and, thus, can be considered valuable therapeutic targets. Preclinical investigations have shown that stem cell-derived exosomes can exert beneficial effects in DN by transferring renoprotective miRs to the injured mesangial cells and podocytes. Of note, renoprotective Exo-miR-125a secreted by adipose-derived mesenchymal stem cells can improve the injured mesangial cells, while renoprotective Exo-miRs secreted by adipose-derived stem cells (Exo-miR-486 and Exo-miR-215-5p), human urine-derived stem cells (Exo-miR-16-5p), and bone marrow-derived mesenchymal stem cells (Exo-miR-let-7a) can improve the injured podocytes. On the other hand, clinical investigations have indicated that circulating Exo-miRs isolated from urine or serum hold great potential as promising biomarkers in DN.

Project description:Diabetic nephropathy (DN), as the one of most common complications of diabetes, is generally diagnosed based on a longstanding duration, albuminuria, and decreased kidney function. Some patients with the comorbidities of diabetes and other primary renal diseases have similar clinical features to DN, which is defined as non-diabetic renal disease (NDRD). It is necessary to distinguish between DN and NDRD, considering they differ in their pathological characteristics, treatment regimes, and prognosis. Renal biopsy provides a gold standard; however, it is difficult for this to be conducted in all patients. Therefore, it is necessary to discover non-invasive biomarkers that can distinguish between DN and NDRD. In this research, the urinary exosomes were isolated from the midstream morning urine based on ultracentrifugation combined with 0.22 μm membrane filtration. Data-independent acquisition-based quantitative proteomics were used to define the proteome profile of urinary exosomes from DN (n = 12) and NDRD (n = 15) patients diagnosed with renal biopsy and Type 2 diabetes mellitus (T2DM) patients without renal damage (n = 9), as well as healthy people (n = 12). In each sample, 3372 ± 722.1 proteins were identified on average. We isolated 371 urinary exosome proteins that were significantly and differentially expressed between DN and NDRD patients, and bioinformatic analysis revealed them to be mainly enriched in the immune and metabolic pathways. The use of least absolute shrinkage and selection operator (LASSO) logistic regression further identified phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) as the differential diagnostic biomarker, the efficacy of which was verified with another cohort including eight DN patients, five NDRD patients, seven T2DM patients, and nine healthy people. Additionally, a concentration above 1.203 μg/L was established for DN based on the ELISA method. Furthermore, of the 19 significantly different expressed urinary exosome proteins selected by using the protein-protein interaction network and LASSO logistic regression, 13 of them were significantly related to clinical indicators that could reflect the level of renal function and hyperglycemic management.

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Urinary exosomal microRNAs in incipient diabetic nephropathy.

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Urinary exosomal microRNAs in incipient diabetic nephropathy.

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