Diabetic Nephropathy: Perspective on Extracellular Vesicles

Abstract

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus. It is the most frequent cause of end-stage renal disease with no definitive therapy available so far. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nano-and micron-sized heterogeneous vesicles that can be secreted by almost all cell types. Importantly, EVs contain many biologically active materials, such as RNAs, DNAs, proteins, and lipids, from their parental cells, which can be transported to their recipient cells to mediate intercellular communication and signaling. Accumulating studies demonstrated that EVs, mainly exosomes and microvesicles, participated in the pathophysiological process of DN. Recently emerging studies also found that the contents of EVs in the urine (miRNAs, mRNAs, and proteins) could be used as potential biomarkers for DN. Therefore, in this mini-review, the generation, isolation methods, and biological function of EVs were introduced, and then the current information about the mechanism and the diagnostic value in the development of DN was summarized. Moreover, the review also discussed the future challenges of exploring the role of EVs in kidney disease.

Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

“…However, in renal and metabolic diseases, urine stands out as a sound alternative for EV studies [ 12 , 36 ]. First, urine collection is noninvasive, fast and easy, and second, it has been postulated that uEVs, coming from all parts of the nephrons and collecting ducts, might mainly be of renal origin, since circulating EVs are not able to pass through the glomerular membrane, at least in physiological conditions [ 10 ]. Therefore, the study of uEV content and distribution might give insights into the physiopathology of DKD, and contribute to the discovery of novel early diagnosis and risk stratification biomarkers, as well as therapeutic targets in this pathology.…”

“…The lack of sensitivity and specificity of albumin for the early identification of high-risk patients has prompted the search for novel noninvasive alternatives to cover this clinical need. EVs, and more precisely uEVs, have emerged as a plausible option in this regard, since the structure of the glomerular membrane, at least in healthy condition, restrains the passage of circulating EVs to urine, and thus uEVs derived from all parts of the nephrons and collecting ducts might be mainly of renal origin [ 10 ]. Likewise, the determination of the total uEV numbers or specific uEV subpopulations, and the analysis of their content might help to identify novel biomarkers and therapeutic targets for DKD risk assessment in every segment of the nephron, serving as early biomarkers of renal dysfunction and structural injury ( Table 2 ).…”

“…The growing incidence of CV morbi-mortality in patients with DKD and the lack of precise biomarkers, other than albuminuria, for outcome assessment in this pathology reveals the need for: (1) novel noninvasive early diagnosis and prognosis candidates for the identification of patients with T2DM with high probability of DKD development and progression, and (2) alternative therapeutic targets to treat these high-risk patients. Extracellular vesicles (EVs) have emerged as useful noninvasive alternatives for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases [ 9 , 10 ]. EVs are lipidic nanospheres actively released to the extracellular space by most cell types, that carry proteins, nucleic acids or metabolites from parental cells participating in cell-to-cell communication processes [ 11 ].…”

What do we know about biomarkers in diabetic kidney disease?

“…Currently, the predictive value for the development of DKD is proven for a number of miRNA types, mRNA (mainly for the Wilms tumour protein 1 [WT1 protein], which plays a major regulatory role in podocyte homeostasis) and proteins (e.g. megalin C, WT1 protein itself, regucalcin, osteoprotegerin, aquaporins 2 and 5, and others) and the constellations of these components, enclosed inside the MV [47,48].…”

Knockdown of the Long Noncoding RNA LUCAT1 Inhibits High-Glucose-Induced Epithelial-Mesenchymal Transition through the miR-199a-5p–ZEB1 Axis in Human Renal Tubular Epithelial Cells

“…Diabetic nephropathy is the main cause of end-stage renal disease, and its major pathologic feature is renal fibrosis [8]. Many studies have indicated that lncRNAs participate in the pathogenesis and progression of diabetic nephropathy [9].…”