A systematic review and Meta-analysis of urinary extracellular vesicles proteome in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a major microvascular complication of both type 1 and type 2 diabetes mellitus and is the most frequent cause of end-stage renal disease with an increasing prevalence. Presently there is no non-invasive method for differential diagnosis, and an efficient target therapy is lacking. Extracellular vesicles (EV), including exosomes, microvesicles, and apoptotic bodies, are present in various body fluids such as blood, cerebrospinal fluid, and urine. Proteins in EV are speculated to be involved in various processes of disease and reflect the original cells’ physiological states and pathological conditions. This systematic review is based on urinary extracellular vesicles studies, which enrolled patients with DN and investigated the proteins in urinary EV. We systematically reviewed articles from the PubMed, Embase, Web of Science databases, and China National Knowledge Infrastructure (CNKI) database until January 4, 2022. The article quality was appraised according to the Newcastle-Ottawa Quality Assessment Scale (NOS). The methodology of samples, isolation and purification techniques of urinary EV, and characterization methods are summarized. Molecular functions, biological processes, and pathways were enriched in all retrievable urinary EV proteins. Protein-protein interaction analysis (PPI) revealed pathways of potential biomarkers. A total of 539 articles were retrieved, and 13 eligible records were enrolled in this systematic review and meta-analysis. And two studies performed mass spectrometry to obtain the proteome profile. Two of them enrolled only T1DM patients, two studies enrolled both patients with T1DM and T2DM, and other the nine studies focused on T2DM patients. In total 988 participants were enrolled, and DN was diagnosed according to UACR, UAER, or decreased GFR. Totally 579 urinary EV proteins were detected and 28 of them showed a potential value to be biomarkers. The results of bioinformatics analysis revealed that urinary EV may participate in DN through various pathways such as angiogenesis, biogenesis of EV, renin-angiotensin system, fluid shear stress and atherosclerosis, collagen degradation, and immune system. Besides that, it is necessary to report results compliant with the guideline of ISEV, in orderto assure repeatability and help for further studies. This systematic review concordance with previous studies and the results of meta-analysis may help to value the methodology details when urinary EV proteins were reported, and also help to deepen the understanding of urinary EV proteins in DN.

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“…Current new biomarkers mainly target diagnoses of inflammation, endothelial damage, fibrosis, endothelial dysfunction, and kidney damage, 141 including TNF-α receptor, 142 intercellular adhesion molecule-1, 143 endostatin, 144 copeptin, 145 kidney injury molecule-1, 146 , 147 monocyte chemoattractant protein-1, 148 and neutrophil gelatinase-associated lipocalins. 149 Extracellular vesicles have recently attracted interest, 150 because they are essentially exosomes and particles 151 that transport miRNA, 152 mRNA, 153 , 154 and proteins, 155 and might serve as early biomarkers of DKD. In addition to individual biomarkers, other approaches such as proteomics, 156 genomics, 157 and metabolomics 158 all play roles in screening, especially in studies of chronic kidney disease (CKD) 159 which can predict the development of proteinuria.…”

Diabetes with kidney injury may change the abundance and cargo of urinary extracellular vesicles

“…uEVs may be involved in the progress of diabetic nephropathy because they carry valuable sources for disease-stage-specific information and have the natural quality of fingerprints in disease progression ( 18 ). However, there are scarce data reported about the application of uEV research in different stages of diabetes ( 19 ). Therefore, we perform this study in order to research the physiological and pathological secretion of uEVs in healthy controls and diabetes patients with and without kidney injury.…”

Urinary exosome proteins PAK6 and EGFR as noninvasive diagnostic biomarkers of diabetic nephropathy

“…Since the detection of urine exosomes, studies demonstrated that urinary exosomes could serve as novel biomarkers reflecting the physiological and pathophysiological state of the human body [ 10 , 11 ]. Furthermore, a recent study suggested that urinary exosomes are engaged in the pathophysiological events related to DN, which could potentially provide promising biomarkers and specific therapeutic targets for DN [ 12 ]. In a word, urinary exosomes are characterized by a variety of features, including cargo transfer to specific target cells, regulation of intercellular crosstalk, and alteration of the biofunction of recipient cells, which manifest important consequences for the pathogenesis, diagnosis, and treatment of DN [ 13 ].…”