Abstract
MicroRNAs (miRNAs) are short non-coding RNA species which are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent´s miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2-fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR-30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-β-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies.
Highlights
Diabetic nephropathy (DN), the most frequent form of chronic kidney disease, is a progressive kidney disease and a major debilitating complication of both type 1 and type 2 diabetes that can lead to end-stage renal disease (ESRD) [1]
Deregulated miR-320c, which might have an impact on the TGF-β-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II diabetic nephropathy (DN) that should be evaluated in future studies
To this end miRNAs were isolated from urinary exosomes from 8 healthy controls (C), 8 patients with T2D and 8 patients with DN and subjected to Agilent microarrays containing all miRNAs from miRBase release 19.0
Summary
Diabetic nephropathy (DN), the most frequent form of chronic kidney disease, is a progressive kidney disease and a major debilitating complication of both type 1 and type 2 diabetes that can lead to end-stage renal disease (ESRD) [1]. The miRNA-30 family is abundantly expressed in podocytes compared to other glomerular cell types [13] and its Smad2-dependent down-regulation [14] facilitates podocyte injury [15]. Glomerular miR-21 expression is positively associated with albumin-creatinine ratio (ACR) in patients with DN and potentially serves as an indicator of podocyte damage [16]. Increased circulating miR-21 levels are associated with kidney fibrosis and correlate with eGFR [17]. It was demonstrated that renal miR-21 levels are positively correlated with estimated glomerular filtration rate (eGFR), proteinuria and glomerulosclerosis in DN patients [18]. The miRNA-29 family protects the kidney from fibrotic damage and the DPP-4 inhibitor linagliptin has been shown to inhibit TGF-β-induced endothelial to mesenchymal transition (EndMT) by restoring miRNA-29s level [19]
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